@article {702, title = {Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study.}, journal = {JAMA}, volume = {288}, year = {2002}, month = {2002 Sep 25}, pages = {1475-83}, abstract = {

CONTEXT: Mild cognitive impairment (MCI) may be a precursor to dementia, at least in some cases. Dementia and MCI are associated with neuropsychiatric symptoms in clinical samples. Only 2 population-based studies exist of the prevalence of these symptoms in dementia, and none exist for MCI.

OBJECTIVE: To estimate the prevalence of neuropsychiatric symptoms in dementia and MCI in a population-based study.

DESIGN: Cross-sectional study derived from the Cardiovascular Health Study, a longitudinal cohort study.

SETTING AND PARTICIPANTS: A total of 3608 participants were cognitively evaluated using data collected longitudinally over 10 years and additional data collected in 1999-2000 in 4 US counties. Dementia and MCI were classified using clinical criteria and adjudicated by committee review by expert neurologists and psychiatrists. A total of 824 individuals completed the Neuropsychiatric Inventory (NPI); 362 were classified as having dementia, 320 as having MCI; and 142 did not meet criteria for MCI or dementia.

MAIN OUTCOME MEASURE: Prevalence of neuropsychiatric symptoms, based on ratings on the NPI in the previous month and from the onset of cognitive symptoms.

RESULTS: Of the 682 individuals with dementia or MCI, 43\% of MCI participants (n = 138) exhibited neuropsychiatric symptoms in the previous month (29\% rated as clinically significant) with depression (20\%), apathy (15\%), and irritability (15\%) being most common. Among the dementia participants, 75\% (n = 270) had exhibited a neuropsychiatric symptom in the past month (62\% were clinically significant); 55\% (n = 199) reported 2 or more and 44\% (n = 159) 3 or more disturbances in the past month. In participants with dementia, the most frequent disturbances were apathy (36\%), depression (32\%), and agitation/aggression (30\%). Eighty percent of dementia participants (n = 233) and 50\% of MCI participants (n = 139) exhibited at least 1 NPI symptom from the onset of cognitive symptoms. There were no differences in prevalence of neuropsychiatric symptoms between participants with Alzheimer-type dementia and those with other dementias, with the exception of aberrant motor behavior, which was more frequent in Alzheimer-type dementia (5.4\% vs 1\%; P =.02).

CONCLUSIONS: Neuropsychiatric symptoms occur in the majority of persons with dementia over the course of the disease. These are the first population-based estimates for neuropsychiatric symptoms in MCI, indicating a high prevalence associated with this condition as well. These symptoms have serious adverse consequences and should be inquired about and treated as necessary. Study of neuropsychiatric symptoms in the context of dementia may improve our understanding of brain-behavior relationships.

}, keywords = {Aged, Aggression, Anxiety, Behavioral Symptoms, Cognition Disorders, Comorbidity, Cross-Sectional Studies, Delusions, Dementia, Depression, Feeding and Eating Disorders, Female, Humans, Longitudinal Studies, Male, Neuropsychological Tests, Prevalence, Sleep Wake Disorders}, issn = {0098-7484}, doi = {10.1001/jama.288.12.1475}, author = {Lyketsos, Constantine G and Lopez, Oscar and Jones, Beverly and Fitzpatrick, Annette L and Breitner, John and DeKosky, Steven} } @article {729, title = {Prospective study of alcohol consumption and risk of dementia in older adults.}, journal = {JAMA}, volume = {289}, year = {2003}, month = {2003 Mar 19}, pages = {1405-13}, abstract = {

CONTEXT: Alcohol consumption has been associated with complex changes in cerebral vasculature and structure in older adults. How alcohol consumption affects the incidence of dementia is less clear.

OBJECTIVE: To determine the prospective relationship of alcohol consumption and risk of dementia among older adults.

DESIGN, SETTING, AND PARTICIPANTS: Nested case-control study of 373 cases with incident dementia and 373 controls who were among 5888 adults aged 65 years and older who participated in the Cardiovascular Health Study, a prospective, population-based cohort study in 4 US communities. The controls were frequency-matched on age, death before 1999, and their attendance of a 1998-1999 clinic. Participants in this study underwent magnetic resonance imaging (MRI) of the brain and cognitive testing between 1992 and 1994 and were followed up until 1999.

MAIN OUTCOME MEASURES: Odds of incident dementia, ascertained by detailed neurological and neuropsychological examinations according to average alcohol consumption, assessed by self-reported intake of beer, wine, and liquor at 2 visits prior to the date of the MRI.

RESULTS: Compared with abstention, the adjusted odds for dementia among those whose weekly alcohol consumption was less than 1 drink were 0.65 (95\% confidence interval [CI], 0.41-1.02); 1 to 6 drinks, 0.46 (95\% CI, 0.27-0.77); 7 to 13 drinks, 0.69 (95\% CI, 0.37-1.31); and 14 or more drinks, 1.22 (95\% CI, 0.60-2.49; P for quadratic term =.001). A trend toward greater odds of dementia associated with heavier alcohol consumption was most apparent among men and participants with an apolipoprotein E epsilon4 allele. We found generally similar relationships of alcohol use with Alzheimer disease and vascular dementia.

CONCLUSIONS: Compared with abstention, consumption of 1 to 6 drinks weekly is associated with a lower risk of incident dementia among older adults.

}, keywords = {Aged, Alcohol Drinking, Apolipoprotein E4, Apolipoproteins E, Brain, Case-Control Studies, Dementia, Female, Humans, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Prospective Studies, Risk}, issn = {0098-7484}, doi = {10.1001/jama.289.11.1405}, author = {Mukamal, Kenneth J and Kuller, Lewis H and Fitzpatrick, Annette L and Longstreth, W T and Mittleman, Murray A and Siscovick, David S} } @article {750, title = {Regional and racial differences in the prevalence of physician-diagnosed essential tremor in the United States.}, journal = {Mov Disord}, volume = {18}, year = {2003}, month = {2003 Sep}, pages = {1035-40}, abstract = {

For reasons that are unclear, prevalence estimates of essential tremor (ET) differ considerably across the United States. Separate communities have never been sampled within the framework of the same study to substantiate these differences. We estimated the prevalence of physician-diagnosed ET in the elderly in four communities in the United States in whom the same screening questions were used, and examined whether this prevalence differed between Caucasians and African Americans. The Cardiovascular Health Study recruited a sample of Medicare beneficiaries >/=65 years of age from four communities in different regions of the United States. In 1998 to 1999, 3,494 participants (mean age, 80.0 years; range, 70-103 years) answered a 12-question screen for ET, including the question, "has a doctor diagnosed you as having familial tremor or benign essential tremor?" Fifty-four participants reported that a doctor had diagnosed them as having ET (1.5\%; 95\% confidence interval, [CI], 1.1-2.0\%). Prevalence was similar across the four communities (1.1-2.0\%). A larger proportion of Caucasians than African Americans reported a diagnosis of ET (1.7\% vs. 0.4\%; odds ratio = 4.9; 95\% CI, 1.2-20.2; P = 0.028). In a logistic regression analysis, physician-diagnosed ET was associated with Caucasian ethnicity (P = 0.038) but not with age, gender, education, mental status or depression scores, income, smoking status, or alcohol consumption. When a standardized screening question was used, the proportion of participants with physician-diagnosed ET was similar across four communities, suggesting that the prevalence of this condition may be less variable than is often reported. Caucasians were five times more likely to have physician-diagnosed ET than were African Americans. This study does not provide an explanation for this difference, which deserves further study.

}, keywords = {African Continental Ancestry Group, Aged, Aged, 80 and over, Essential Tremor, European Continental Ancestry Group, Female, Humans, Male, Physicians, Prevalence, United States}, issn = {0885-3185}, doi = {10.1002/mds.10492}, author = {Louis, Elan D and Fried, Linda P and Fitzpatrick, Annette L and Longstreth, William T and Newman, Anne B} } @article {805, title = {Barriers to health care access among the elderly and who perceives them.}, journal = {Am J Public Health}, volume = {94}, year = {2004}, month = {2004 Oct}, pages = {1788-94}, abstract = {

OBJECTIVES: We evaluated self-perceived access to health care in a cohort of Medicare beneficiaries.

METHODS: We identified patterns of use and barriers to health care from self-administered questionnaires collected during the 1993-1994 annual examination of the Cardiovascular Health Study.

RESULTS: The questionnaires were completed by 4889 (91.1\%) participants, with a mean age of 76.0 years. The most common barriers to seeing a physician were the doctor{\textquoteright}s lack of responsiveness to patient concerns, medical bills, transportation, and street safety. Low income, no supplemental insurance, older age, and female gender were independently related to perceptions of barriers. Race was not significant after adjustment for other factors.

CONCLUSIONS: Psychological and physical barriers affect access to care among the elderly; these may be influenced by poverty more than by race.

}, keywords = {Aged, Aged, 80 and over, Chi-Square Distribution, Female, Health Behavior, Health Services Accessibility, Humans, Logistic Models, Male, Medicare, Patients, Surveys and Questionnaires, United States}, issn = {0090-0036}, doi = {10.2105/ajph.94.10.1788}, author = {Fitzpatrick, Annette L and Powe, Neil R and Cooper, Lawton S and Ives, Diane G and Robbins, John A} } @article {762, title = {Incidence and prevalence of dementia in the Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {52}, year = {2004}, month = {2004 Feb}, pages = {195-204}, abstract = {

OBJECTIVES: To estimate the incidence and prevalence of dementia, Alzheimer{\textquoteright}s disease (AD), and vascular dementia (VaD) in the Cardiovascular Health Study (CHS) cohort.

DESIGN: Longitudinal cohort study using prospectively and retrospectively collected data to evaluate dementia.

SETTING: Four U.S. communities.

PARTICIPANTS: There were 3,602 CHS participants, including 2,865 white and 492 African-American participants free of dementia, who completed a cranial magnetic resonance image between 1992 and 1994 and were followed for an average of 5.4 years.

MEASUREMENTS: Dementia was classified by neurologist/psychiatrist committee review using neuropsychological tests, neurological examinations, medical records, physician questionnaires, and proxy/informant interviews. Demographics and apolipoprotein E (APOE) genotype were collected at baseline. Incidence by type of dementia was determined using National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer{\textquoteright}s Disease and Related Disorders Association criteria for AD and Alzheimer{\textquoteright}s Disease Diagnostic and Treatment Center{\textquoteright}s State of California criteria for VaD.

RESULTS: Classification resulted in 227 persons with prevalent dementia at entry into the study and 480 incident cases during follow-up. Incidence rates of dementia scaled to age 80 were 34.7 per 1,000 person-years for white women, 35.3 for white men, 58.8 for African-American women, and 53.0 for African-American men. Sex differences were not significant within race. Adjusted for age and education, racial differences were only of borderline significance and may have been influenced by ascertainment methodology. Rates differed substantially by educational attainment but were only significant for whites. Those with the APOE epsilon4 allele had an incidence rate at age 80 of 56.4, compared with 29.6 for those without this allele (P<.001). In whites, type-specific incidence at age 80 was 19.2 for AD versus 14.6 for VaD. These rates were 34.7 and 27.2 for African Americans. At termination of observation, women had only a slightly higher prevalence of dementia (16.0\%) than men (14.7\%).

CONCLUSION: Sex and racial differences were not found, and VaD was higher than reported in other studies. These data provide new estimates of dementia incidence in a community sample for projection of future burden.

}, keywords = {African Americans, Age Distribution, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Dementia, Dementia, Vascular, Education, European Continental Ancestry Group, Female, Humans, Incidence, Longitudinal Studies, Male, Prevalence, Proportional Hazards Models, Risk Factors, Sex Distribution, United States}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2004.52058.x}, author = {Fitzpatrick, Annette L and Kuller, Lewis H and Ives, Diane G and Lopez, Oscar L and Jagust, William and Breitner, John C S and Jones, Beverly and Lyketsos, Constantine and Dulberg, Corinne} } @article {821, title = {Association between screening for osteoporosis and the incidence of hip fracture.}, journal = {Ann Intern Med}, volume = {142}, year = {2005}, month = {2005 Feb 01}, pages = {173-81}, abstract = {

BACKGROUND: Because direct evidence for the effectiveness of screening is lacking, guidelines disagree on whether people should be screened for osteoporosis.

OBJECTIVE: To determine whether population-based screening for osteoporosis in older adults is associated with fewer incident hip fractures than usual medical care.

DESIGN: Nonconcurrent cohort study.

SETTING: Population-based cohort enrolled in the Cardiovascular Health Study (CHS) from 4 states (California, Pennsylvania, Maryland, and North Carolina).

PATIENTS: 3107 adults 65 years of age and older who attended their CHS study visits in 1994-1995.

MEASUREMENTS: 31 participant characteristics (including demographic characteristics, medical histories, medications, and physical examination findings) and incident hip fractures over 6 years of follow-up.

INTERVENTION: Bone density scans (dual-energy x-ray absorptiometry [DEXA] at the hip) for participants in California and Pennsylvania (n = 1422) and usual care for participants in Maryland and North Carolina (n = 1685).

RESULTS: The incidence of hip fractures per 1000 person-years was 4.8 in the screened group and 8.2 in the usual care group. Screening was associated with a statistically significant lower hazard of hip fracture than usual care after adjustment for sex and propensity to be screened (Cox proportional hazard ratio, 0.64 [95\% CI, 0.41 to 0.99]).

LIMITATIONS: The mechanism of the association was unclear. A small unmeasured confounder that decreased the hazard of hip fracture could diminish or erase the observed association.

CONCLUSIONS: Use of hip DEXA scans to screen for osteoporosis in older adults was associated with 36\% fewer incident hip fractures over 6 years compared with usual medical care. Further research is needed to explore the mechanism of this association.

}, keywords = {Absorptiometry, Photon, Aged, Aged, 80 and over, Cohort Studies, Female, Hip Fractures, Humans, Incidence, Male, Mass Screening, Osteoporosis, Risk Factors, Sensitivity and Specificity}, issn = {1539-3704}, doi = {10.7326/0003-4819-142-3-200502010-00007}, author = {Kern, Lisa M and Powe, Neil R and Levine, Michael A and Fitzpatrick, Annette L and Harris, Tamara B and Robbins, John and Fried, Linda P} } @article {852, title = {Dementia and Alzheimer{\textquoteright}s disease incidence in relationship to cardiovascular disease in the Cardiovascular Health Study cohort.}, journal = {J Am Geriatr Soc}, volume = {53}, year = {2005}, month = {2005 Jul}, pages = {1101-7}, abstract = {

OBJECTIVES: To determine whether coronary artery disease, peripheral arterial disease (PAD), or noninvasive markers of cardiovascular disease (CVD) predict the onset of dementia and Alzheimer{\textquoteright}s disease (AD).

DESIGN: Longitudinal cohort study.

SETTING: Four U.S. communities.

PARTICIPANTS: Men and women (N=3,602) with a brain magnetic resonance imaging (MRI) scan but no dementia were followed for 5.4 years. Participants with stroke were excluded.

MEASUREMENTS: Neurologists and psychiatrists classified incident cases of dementia and subtype using neuropsychological tests, examination, medical records and informant interviews. CVD was defined at the time of the MRI scan. Noninvasive tests of CVD were assessed within 1 year of the MRI. Apolipoprotein E allele status, age, race, sex, education, Mini-Mental State Examination score, and income were assessed as potential confounders.

RESULTS: The incidence of dementia was higher in those with prevalent CVD, particularly in the subgroup with PAD. The rate of AD was 34.4 per 1,000 person-years for those with a history of CVD, versus 22.2 per 1,000 person-years without a history of CVD (adjusted hazard ratio (HR)=1.3, 95\% confidence interval (CI)=1.0-1.7). Rates of AD were highest in those with PAD (57.4 vs 23.7 per 100 person-years, adjusted HR=2.4, 95\% CI=1.4-4.2). Results were similar with further exclusion of those with vascular dementia from the AD group. A gradient of increasing risk was noted with the extent of vascular disease.

CONCLUSION: Older adults with CVD other than stroke had a higher risk of dementia and AD than did those without CVD. The risk was highest in people with PAD, suggesting that extensive peripheral atherosclerosis is a risk factor for AD.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Cardiovascular Diseases, Cohort Studies, Coronary Disease, Dementia, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Peripheral Vascular Diseases, Risk Factors}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2005.53360.x}, author = {Newman, Anne B and Fitzpatrick, Annette L and Lopez, Oscar and Jackson, Sharon and Lyketsos, Constantine and Jagust, William and Ives, Diane and DeKosky, Steven T and Kuller, Lewis H} } @article {846, title = {Statin use and the risk of incident dementia: the Cardiovascular Health Study.}, journal = {Arch Neurol}, volume = {62}, year = {2005}, month = {2005 Jul}, pages = {1047-51}, abstract = {

BACKGROUND: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduce cardiovascular risk through mechanisms that might affect the development of dementia.

OBJECTIVE: To evaluate whether statin use is associated with a lower risk of dementia compared with never use of lipid-lowering agents (LLAs).

DESIGN: Cohort study of community-dwelling adults 65 years and older. The analysis included 2798 participants free of dementia at baseline.

MAIN OUTCOME MEASURES: Using Cox proportional hazards regression analysis, we estimated the risk of incident all-cause and type-specific dementia associated with time-dependent statin therapy compared with never use of LLAs. The primary analyses incorporated a 1-year lag between exposure and outcome. Secondary analyses included the final year of exposure and modeled statin use as current use vs nonuse to simulate a case-control approach.

RESULTS: Compared with never use of LLAs, ever use of statins was not associated with the risk of all-cause dementia (multivariable-adjusted hazard ratio [HR], 1.08; 95\% confidence interval [CI], 0.77-1.52), Alzheimer disease alone (HR, 1.21; 95\% CI, 0.76-1.91), mixed Alzheimer disease and vascular dementia (HR, 0.87; 95\% CI, 0.44-1.72), or vascular dementia alone (HR, 1.36; 95\% CI, 0.61-3.06). In contrast, in secondary analyses, current use of statins compared with nonuse of LLAs was associated with HRs of 0.69 (95\% CI, 0.46-1.02) for all-cause dementia and 0.56 (95\% CI, 0.35-0.92) for any Alzheimer disease.

CONCLUSIONS: In this cohort study, statin therapy was not associated with a decreased risk of dementia. Methodological differences may explain why results of this cohort investigation differ from those of prior case-control studies. Additional investigation is needed to determine whether and for whom statin use may affect dementia risk.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cohort Studies, Dementia, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipidemias, Male}, issn = {0003-9942}, doi = {10.1001/archneur.62.7.1047}, author = {Rea, Thomas D and Breitner, John C and Psaty, Bruce M and Fitzpatrick, Annette L and Lopez, Oscar L and Newman, Anne B and Hazzard, William R and Zandi, Peter P and Burke, Gregory L and Lyketsos, Constantine G and Bernick, Charles and Kuller, Lewis H} } @article {823, title = {Survival following dementia onset: Alzheimer{\textquoteright}s disease and vascular dementia.}, journal = {J Neurol Sci}, volume = {229-230}, year = {2005}, month = {2005 Mar 15}, pages = {43-9}, abstract = {

Survival following the onset of dementia has been reported to vary from 3 to over 9 years. We examined mortality in 3602 participants of the Cardiovascular Health (CHS) Cognition Study in four US communities evaluated for dementia incidence between 1992 and 1999 and followed for 6.5 years. By June 2000, 33 of 62 (53.2\%) participants who developed vascular dementia (VaD) had died compared to 79 of 245 (32.2\%) with Alzheimer{\textquoteright}s disease (AD), 66 of 151 (43.7\%) with both AD and VaD, and 429 of 2318 (18.5\%) with normal cognition. Using Cox proportional hazards regression with a time-dependent covariate for dementia status adjusted for age, gender and race, individuals with VaD were more than four times as likely to die during follow-up than those with normal cognition (HR: 4.4, 95\% CI: 3.1-6.3). The hazard ratios were 2.1 (95\% CI: 1.6-2.7) for AD and 2.5 (95\% CI: 1.9-3.3) for both types. Adjusted accelerated life models estimated median survival from dementia onset to death as 3.9 years for those with VaD, 7.1 years for AD, 5.4 years for mixed dementia, and 11.0 years for matched controls with normal cognition. While persons with VaD died primarily from cerebrovascular disease, those with AD/mixed dementia died more frequently from dementia/failure to thrive.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Brain, Capillaries, Cerebral Amyloid Angiopathy, Cerebrovascular Circulation, Cerebrovascular Disorders, Female, Frontal Lobe, Humans, Male, Middle Aged, Prospective Studies}, issn = {0022-510X}, doi = {10.1016/j.jns.2004.11.022}, author = {Fitzpatrick, Annette L and Kuller, Lewis H and Lopez, Oscar L and Kawas, Claudia H and Jagust, William} } @article {899, title = {Education, cognitive test scores, and black-white differences in dementia risk.}, journal = {J Am Geriatr Soc}, volume = {54}, year = {2006}, month = {2006 Jun}, pages = {898-905}, abstract = {

OBJECTIVES: To compare dementia risks of elderly black and white subjects and to determine whether differences in education and cognitive test scores contribute to the inconsistency in reported differences between these groups.

DESIGN: Longitudinal, 6-year follow-up.

PARTICIPANTS: Two thousand seven hundred eighty-six older black and white subjects in the Cardiovascular Health Study.

MEASUREMENTS: Age, education (>10 years vs < or =10 years), Modified Mini-Mental State Examination score (3MS, < or =85 vs >85). Potential confounders were sex, depression, apolipoprotein E4 genotype, vascular disease, and baseline magnetic resonance imaging changes.

RESULTS: White subjects with low education and black subjects with high education had twice the risk of dementia of white subjects with high education (95\% confidence interval (CI)=1.5-2.4 and 95\% CI=1.4-2.7); black subjects with low education had five times the risk of dementia (95\% CI=3.4-7.7). Likewise, for subjects with low 3MSE scores, black subjects had 6.7 times the risk of dementia (95\% CI=4.7-9.7) and white subjects had 2.7 times the risk of dementia (95\% CI=2.2-3.5) as white subjects with high 3MSE scores. Finally, in Cox models, there was no significant black-white difference in dementia risk after adjustment for all confounders and baseline 3MSE.

CONCLUSION: Black race was associated with greater dementia risk even after adjustment for education and other potential confounders. This black-white difference in dementia risk was markedly attenuated after adjustment for baseline cognitive screening scores. The apparent race effect may reflect gaps in the quality of education or differences in the trajectory of impaired cognitive function experienced by the two groups. Future investigations might take these findings into consideration for the design of studies evaluating black-white differences in dementia risk.

}, keywords = {African Continental Ancestry Group, Aged, Cognition, Dementia, Educational Status, European Continental Ancestry Group, Female, Follow-Up Studies, Humans, Incidence, Male, Psychological Tests, Retrospective Studies, Risk Factors, United States}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2006.00747.x}, author = {Shadlen, Marie-Florence and Siscovick, David and Fitzpatrick, Annette L and Dulberg, Corinne and Kuller, Lewis H and Jackson, Sharon} } @article {883, title = {Genetic Susceptibility to Prostate Cancer: Prostate-specific Antigen and its Interaction with the Androgen Receptor (United States).}, journal = {Cancer Causes Control}, volume = {17}, year = {2006}, month = {2006 Mar}, pages = {187-97}, abstract = {

OBJECTIVE: To determine whether directly observed prostate-specific antigen (PSA) promoter diploid haplotype, either alone or in conjunction with androgen receptor (AR) genotype, is associated with prostate cancer risk.

METHODS: We conducted a case-control study nested within the US population-based Cardiovascular Health Study cohort. Incident prostate cancers were identified by linkage to cancer registry records for the years 1989-2000. We genotyped 193 cases and 391 controls for the PSA -252 G/A and -158 G/A SNPs and the AR CAG microsatellite, and developed methods to directly determine proximal PSA promoter haplotypes. Exact logistic regression was used to estimate odds ratios and significance levels.

RESULTS: No significant associations were observed between PSA diplotype and prostate cancer overall. Short (< 20) AR CAG repeat lengths were associated with modest increases in the risk of prostate cancer (OR, 1.46; 95\% CI, 0.97-2.19; p = 0.071) that were significant for advanced disease (OR, 1.82; 95\% CI, 1.02-3.26; p = 0.044). Men who possessed two copies of the PSA*2 (-252G/-158G) haplotype and short AR CAG repeat lengths had a 4-fold (95\% CI, 1.05-20.75; exact p = 0.040) increased risk of prostate cancer, and a 7-fold (95\% CI, 1.25-39.78; exact p = 0.026) increased risk of advanced disease.

CONCLUSIONS: We found evidence that the PSA*2*2 diplotype in combination with short AR CAG alleles increases a man{\textquoteright}s risk of developing prostate cancer. These findings support an etiologic role in prostate cancer of genetic interactions between polymorphisms that increase AR transactivation strength and those that alter the regulatory regions of target genes such as PSA that are responsive to androgen stimulation.

}, keywords = {Aged, Biomarkers, Tumor, Case-Control Studies, Cohort Studies, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Male, Polymorphism, Genetic, Prostate-Specific Antigen, Prostatic Neoplasms, Receptors, Androgen, United States}, issn = {0957-5243}, doi = {10.1007/s10552-005-0454-8}, author = {Sieh, Weiva and Edwards, Karen L and Fitzpatrick, Annette L and Srinouanprachanh, Sengkeo L and Farin, Fred M and Monks, Stephanie A and Kronmal, Richard A and Eaton, David L} } @article {922, title = {Leukocyte telomere length and cardiovascular disease in the cardiovascular health study.}, journal = {Am J Epidemiol}, volume = {165}, year = {2007}, month = {2007 Jan 01}, pages = {14-21}, abstract = {

The telomere length of replicating somatic cells is inversely correlated with age and has been reported to be associated cross-sectionally with cardiovascular disease (CVD). Leukocyte telomere length, as expressed by mean terminal restriction fragment (TRF) length, was measured in 419 randomly selected participants from the Cardiovascular Health Study, comprising a community-dwelling cohort recruited in four US communities. The authors investigated associations between TRF length and selected measures of subclinical CVD/risk factors for CVD (data were collected at the 1992/1993 clinic visit) and incident CVD (ascertained through June 2002). In these participants (average age = 74.2 years (standard deviation, 5.2)), mean TRF length was 6.3 kilobase pairs (standard deviation, 0.62). Significant or borderline inverse associations were found between TRF length and diabetes, glucose, insulin, diastolic blood pressure, carotid intima-media thickness, and interleukin-6. Associations with body size and C-reactive protein were modified by gender and age, occurring only in men and in participants aged 73 years or younger. In younger (but not older) participants, each shortened kilobase pair of TRF corresponded with a threefold increased risk of myocardial infarction (hazard ratio = 3.08, 95\% confidence interval: 1.22, 7.73) and stroke (hazard ratio = 3.22, 95\% confidence interval: 1.29, 8.02). These results support the hypotheses that telomere attrition may be related to diseases of aging through mechanisms involving oxidative stress, inflammation, and progression to CVD.

}, keywords = {Aged, Cardiovascular Diseases, DNA, Female, Humans, Inflammation, Leukocytes, Male, Myocardial Infarction, Oxidative Stress, Pilot Projects, Polymorphism, Restriction Fragment Length, Risk, Risk Assessment, Risk Factors, Telomere}, issn = {0002-9262}, doi = {10.1093/aje/kwj346}, author = {Fitzpatrick, Annette L and Kronmal, Richard A and Gardner, Jeffrey P and Psaty, Bruce M and Jenny, Nancy S and Tracy, Russell P and Walston, Jeremy and Kimura, Masyuki and Aviv, Abraham} } @article {1032, title = {Albuminuria and dementia in the elderly: a community study.}, journal = {Am J Kidney Dis}, volume = {52}, year = {2008}, month = {2008 Aug}, pages = {216-26}, abstract = {

BACKGROUND: Dementia is associated with microvascular disease of the retina. In this study, we examine whether cognitive status (normal cognition, mild cognitive impairment, and dementia) is associated with albuminuria, a microvascular disorder of the kidney.

STUDY DESIGN: Cross-sectional analysis.

SETTING \& PARTICIPANTS: 2,316 participants from the Cardiovascular Health Cognition Study who underwent brain magnetic resonance imaging and testing for albuminuria.

PREDICTOR: Doubling of albuminuria.

OUTCOME: Dementia defined according to neuropsychological and clinical evaluation.

MEASUREMENTS: Multinomial logistic modeling was used to estimate odds ratios (ORs) and 95\% confidence intervals (CIs) of dementia and mild cognitive impairment with doubling of albuminuria compared with the odds with normal cognition.

RESULTS: 283 participants (12.2\%) had dementia, 344 (14.9\%) had mild cognitive impairment, and 1,689 (72.9\%) had normal cognition. Compared with participants with normal cognition, doubling of albuminuria was associated with increased odds of dementia (OR, 1.22; 95\% CI, 1.15 to 1.29). Adjustment for prevalent cardiovascular disease and cardiovascular risk factors, lipid levels, C-reactive protein level, estimated glomerular filtration rate, and apolipoprotein E-4 genotype attenuated this association, but it remained statistically significant (OR, 1.12; 95\% CI, 1.03 to 1.22). Mild cognitive impairment was associated with albuminuria on unadjusted analysis, but not with adjustment for other factors.

LIMITATIONS: Results are cross-sectional; causality cannot be imputed.

CONCLUSIONS: The odds of dementia increased in the presence of albuminuria. These findings suggest a role of shared susceptibility for microvascular disease in the brain and kidney in older adults.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Albuminuria, Brain, Cognition, Cross-Sectional Studies, Dementia, Female, Humans, Incidence, Magnetic Resonance Imaging, Male, Odds Ratio, Population Surveillance, Prognosis, Retrospective Studies, Risk Factors}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2007.12.044}, author = {Barzilay, Joshua I and Fitzpatrick, Annette L and Luchsinger, Jose and Yasar, Sevil and Bernick, Charles and Jenny, Nancy S and Kuller, Lewis H} } @article {1009, title = {Enhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE epsilon4: the Cardiovascular Health Study Cognition Study.}, journal = {Arch Neurol}, volume = {65}, year = {2008}, month = {2008 Jan}, pages = {89-93}, abstract = {

BACKGROUND: Diabetes and the apolipoprotein E epsilon4 allele (APOE epsilon4) increase the risk for Alzheimer disease (AD). We hypothesize that APOE epsilon4 may modify the risk for AD in individuals with diabetes.

OBJECTIVE: To examine the joint effect of type 2 diabetes and APOE epsilon4 on the risk of AD, AD with vascular dementia (mixed AD), and vascular dementia without AD.

DESIGN: The Cardiovascular Health Study (CHS) Cognition Study (1992-2000) is a prospective study designed to identify all existing and new cases of dementia among study participants. Diagnoses were made according to international criteria for dementia and subtypes. There were 2547 dementia-free participants in the CHS Cognition Study cohort with complete information on APOE epsilon4 and type 2 diabetes status; among these, 411 new cases of dementia developed. Risk of dementia was estimated with a Cox proportional hazard model adjusted for age and other demographic and cardiovascular risk factors.

RESULTS: Compared with those who had neither type 2 diabetes nor APOE epsilon4, those with both factors had a significantly higher risk of AD (hazard ratio, 4.58; 95\% confidence interval, 2.18-9.65) and mixed AD (hazard ratio, 3.89; 95\% confidence interval, 1.46-10.40).

CONCLUSION: These data suggest that having both diabetes and APOE epsilon4 increases the risk of dementia, especially for AD and mixed AD.

}, keywords = {African Americans, Age Factors, Aged, Alzheimer Disease, Apolipoprotein E4, Cognition, Cohort Studies, Confidence Intervals, Dementia, Vascular, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Genotype, Humans, Longitudinal Studies, Male, Neuropsychological Tests, Proportional Hazards Models, Prospective Studies, Risk Factors, Sex Factors}, issn = {0003-9942}, doi = {10.1001/archneurol.2007.29}, author = {Irie, Fumiko and Fitzpatrick, Annette L and Lopez, Oscar L and Kuller, Lewis H and Peila, Rita and Newman, Anne B and Launer, Lenore J} } @article {1088, title = {Insulin-like growth factors and leukocyte telomere length: the cardiovascular health study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {64}, year = {2009}, month = {2009 Nov}, pages = {1103-6}, abstract = {

The insulin-like growth factor (IGF) axis may affect immune cell replicative potential and telomere dynamics. Among 551 adults 65 years and older, leukocyte telomere length (LTL), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-binding proteins 1 and 3 (IGFBP-1, IGFBP-3) were measured. Multivariate linear regression was used to model the association of LTL with IGF-1 and IGFBPs, while controlling for confounding and increasing precision by adjusting for covariates. We observed a significant association between higher IGF-1 and longer LTL after adjustment for age, sex, race, smoking status, body mass index, hypertension, diabetes, and serum lipids. The results suggested an increase of .08 kb in LTL for each standard deviation increase of IGF-1 (p = .04). IGFBP-1 and IGFBP-3 were not significantly associated with LTL. High IGF-1 may be an independent predictor of longer LTL, consistent with prior evidence suggesting a role for IGF-1 in mechanisms relating to telomere maintenance.

}, keywords = {Aged, Aging, Cross-Sectional Studies, Female, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I, Leukocytes, Linear Models, Male, Sex Characteristics, Telomere}, issn = {1758-535X}, doi = {10.1093/gerona/glp036}, author = {Kaplan, Robert C and Fitzpatrick, Annette L and Pollak, Michael N and Gardner, Jeffrey P and Jenny, Nancy S and McGinn, Aileen P and Kuller, Lewis H and Strickler, Howard D and Kimura, Masayuki and Psaty, Bruce M and Aviv, Abraham} } @article {1085, title = {Midlife and late-life obesity and the risk of dementia: cardiovascular health study.}, journal = {Arch Neurol}, volume = {66}, year = {2009}, month = {2009 Mar}, pages = {336-42}, abstract = {

BACKGROUND: While high adiposity in middle age appears to be related to greater dementia risk, studies exploring this association in the elderly are conflicting.

OBJECTIVE: To evaluate associations between midlife and late-life obesity and risk of dementia.

DESIGN: Prospective study with mean follow-up of 5.4 years (1992-1994 through 1999).

SETTING: Community-dwelling sample in 4 US sites recruited from Medicare eligibility files.

PARTICIPANTS: A total of 2798 adults without dementia (mean age, 74.7 years; 59.1\% women) participating in the Cardiovascular Health Study who underwent magnetic resonance imaging were measured for height and weight at baseline at age 65 years or older (late life), and self-reported weight at age 50 years (midlife). Body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) was calculated at both times.

MAIN OUTCOME MEASURES: Dementia, Alzheimer disease, and vascular dementia classified by a multidisciplinary committee using standardized criteria.

RESULTS: Classification resulted in 480 persons with incident dementia, 245 with Alzheimer disease (no vascular dementia), and 213 with vascular dementia (with or without Alzheimer disease). In evaluations of midlife obesity, an increased risk of dementia was found for obese (BMI >30) vs normal-weight (BMI 20-25) persons, adjusted for demographics (hazard ratio [HR], 1.39; 95\% confidence interval [CI], 1.03-1.87) and for cardiovascular risk factors (1.36; 0.94-1.95). The risk estimates were reversed in assessments of late-life BMI. Underweight persons (BMI <20) had an increased risk of dementia (1.62; 1.02-2.64), whereas being overweight (BMI >25-30) was not associated (0.92; 0.72-1.18) and being obese reduced the risk of dementia (0.63; 0.44-0.91) compared with those with normal BMI.

CONCLUSION: These results help explain the "obesity paradox" as differences in dementia risk across time are consistent with physical changes in the trajectory toward disability.

}, keywords = {Aged, Aged, 80 and over, Aging, Alzheimer Disease, Anthropometry, Body Mass Index, Dementia, Vascular, Evaluation Studies as Topic, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Obesity, Prospective Studies, Risk, Survival Analysis}, issn = {1538-3687}, doi = {10.1001/archneurol.2008.582}, author = {Fitzpatrick, Annette L and Kuller, Lewis H and Lopez, Oscar L and Diehr, Paula and O{\textquoteright}Meara, Ellen S and Longstreth, W T and Luchsinger, Jos{\'e} A} } @article {1212, title = {Cognition and the risk of hospitalization for serious falls in the elderly: results from the Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {65}, year = {2010}, month = {2010 Nov}, pages = {1242-9}, abstract = {

BACKGROUND: Many elderly adults fall every year, sometimes resulting in serious injury and hospitalization. Although impaired cognition is a risk factor for injurious falls, little is known about cognitive decline above the threshold of impairment and risk of serious falls in community-dwelling seniors.

METHODS: In total, 702 of 5,356 older adults participating in the Cardiovascular Health Study experienced an injurious fall between 1990 and 2005, as indicated by hospitalization records. General cognition was measured annually with the Modified Mini-Mental State Examination and processing speed with the Digit Symbol Substitution Test. The Cox regression model was used to calculate hazard ratio and 95\% confidence interval with and without time-dependent covariates and adjusted for known risk factors.

RESULTS: Participants with slightly decreased Digit Symbol Substitution Test scores were at increased risk for a serious fall (hazard ratio = 1.58, 95\% confidence interval = 1.15-2.17). The risk continued to increase with each quartile decrease in Digit Symbol Substitution Test score. Participants without prevalent cardiovascular disease at baseline and decreased Modified Mini-Mental State Examination scores (80-89) had a 45\% increased risk for a serious fall and those at high risk for dementia (<80) were at twice the risk as participants scoring above 90 (hazard ratio = 2.16, 95\% confidence interval = 1.60-2.91).

CONCLUSIONS: Both decreased general cognition and decreased processing speed appear to be potential risk factors for serious falls in the elderly. When assessing the risk of serious falls in elderly patients, clinicians should consider usual factors like gait instability and sensory impairment as well as less obvious ones such as cardiovascular disease and cognitive function in nondemented adults.

}, keywords = {Accidental Falls, Aged, Aged, 80 and over, Chi-Square Distribution, Cognition Disorders, Female, Follow-Up Studies, Geriatric Assessment, Hospitalization, Humans, Male, Mental Status Schedule, Physical Examination, Proportional Hazards Models, Risk Assessment, Risk Factors, Surveys and Questionnaires}, issn = {1758-535X}, doi = {10.1093/gerona/glq115}, author = {Welmerink, Diana B and Longstreth, W T and Lyles, Mary F and Fitzpatrick, Annette L} } @article {1199, title = {Genome-wide analysis of genetic loci associated with Alzheimer disease.}, journal = {JAMA}, volume = {303}, year = {2010}, month = {2010 May 12}, pages = {1832-40}, abstract = {

CONTEXT: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD).

OBJECTIVES: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases).

DESIGN, SETTING, AND PARTICIPANTS: In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009.

MAIN OUTCOME MEASURE: Presence of Alzheimer disease.

RESULTS: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95\% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95\% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study).

CONCLUSIONS: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.

}, keywords = {Age of Onset, Aged, Alzheimer Disease, Case-Control Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Odds Ratio, Polymorphism, Single Nucleotide}, issn = {1538-3598}, doi = {10.1001/jama.2010.574}, author = {Seshadri, Sudha and Fitzpatrick, Annette L and Ikram, M Arfan and DeStefano, Anita L and Gudnason, Vilmundur and Boada, Merce and Bis, Joshua C and Smith, Albert V and Carassquillo, Minerva M and Lambert, Jean Charles and Harold, Denise and Schrijvers, Elisabeth M C and Ramirez-Lorca, Reposo and Debette, Stephanie and Longstreth, W T and Janssens, A Cecile J W and Pankratz, V Shane and Dartigues, Jean Fran{\c c}ois and Hollingworth, Paul and Aspelund, Thor and Hernandez, Isabel and Beiser, Alexa and Kuller, Lewis H and Koudstaal, Peter J and Dickson, Dennis W and Tzourio, Christophe and Abraham, Richard and Antunez, Carmen and Du, Yangchun and Rotter, Jerome I and Aulchenko, Yurii S and Harris, Tamara B and Petersen, Ronald C and Berr, Claudine and Owen, Michael J and Lopez-Arrieta, Jesus and Varadarajan, Badri N and Becker, James T and Rivadeneira, Fernando and Nalls, Michael A and Graff-Radford, Neill R and Campion, Dominique and Auerbach, Sanford and Rice, Kenneth and Hofman, Albert and Jonsson, Palmi V and Schmidt, Helena and Lathrop, Mark and Mosley, Thomas H and Au, Rhoda and Psaty, Bruce M and Uitterlinden, Andr{\'e} G and Farrer, Lindsay A and Lumley, Thomas and Ruiz, Agustin and Williams, Julie and Amouyel, Philippe and Younkin, Steve G and Wolf, Philip A and Launer, Lenore J and Lopez, Oscar L and van Duijn, Cornelia M and Breteler, Monique M B} } @article {1192, title = {Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology.}, journal = {Proc Natl Acad Sci U S A}, volume = {107}, year = {2010}, month = {2010 May 18}, pages = {9293-8}, abstract = {

Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P < 5 x 10(-8)). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.

}, keywords = {Cohort Studies, Genome-Wide Association Study, Genotype, Humans, Leukocytes, Polymorphism, Single Nucleotide, Receptors, CXCR4, Telomere, Telomere-Binding Proteins}, issn = {1091-6490}, doi = {10.1073/pnas.0911494107}, author = {Levy, Daniel and Neuhausen, Susan L and Hunt, Steven C and Kimura, Masayuki and Hwang, Shih-Jen and Chen, Wei and Bis, Joshua C and Fitzpatrick, Annette L and Smith, Erin and Johnson, Andrew D and Gardner, Jeffrey P and Srinivasan, Sathanur R and Schork, Nicholas and Rotter, Jerome I and Herbig, Utz and Psaty, Bruce M and Sastrasinh, Malinee and Murray, Sarah S and Vasan, Ramachandran S and Province, Michael A and Glazer, Nicole L and Lu, Xiaobin and Cao, Xiaojian and Kronmal, Richard and Mangino, Massimo and Soranzo, Nicole and Spector, Tim D and Berenson, Gerald S and Aviv, Abraham} } @article {1179, title = {A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {65}, year = {2010}, month = {2010 May}, pages = {478-87}, abstract = {

BACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity.

METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort.

RESULTS: There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 x 10(-8). Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage.

CONCLUSION: Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.

}, keywords = {Adult, Age Factors, Aged, Aged, 80 and over, Alleles, Cohort Studies, Confidence Intervals, Female, Genome-Wide Association Study, Genotype, Humans, Longevity, Male, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide}, issn = {1758-535X}, doi = {10.1093/gerona/glq028}, author = {Newman, Anne B and Walter, Stefan and Lunetta, Kathryn L and Garcia, Melissa E and Slagboom, P Eline and Christensen, Kaare and Arnold, Alice M and Aspelund, Thor and Aulchenko, Yurii S and Benjamin, Emelia J and Christiansen, Lene and D{\textquoteright}Agostino, Ralph B and Fitzpatrick, Annette L and Franceschini, Nora and Glazer, Nicole L and Gudnason, Vilmundur and Hofman, Albert and Kaplan, Robert and Karasik, David and Kelly-Hayes, Margaret and Kiel, Douglas P and Launer, Lenore J and Marciante, Kristin D and Massaro, Joseph M and Miljkovic, Iva and Nalls, Michael A and Hernandez, Dena and Psaty, Bruce M and Rivadeneira, Fernando and Rotter, Jerome and Seshadri, Sudha and Smith, Albert V and Taylor, Kent D and Tiemeier, Henning and Uh, Hae-Won and Uitterlinden, Andr{\'e} G and Vaupel, James W and Walston, Jeremy and Westendorp, Rudi G J and Harris, Tamara B and Lumley, Thomas and van Duijn, Cornelia M and Murabito, Joanne M} } @article {1279, title = {Association of HSP70 and its co-chaperones with Alzheimer{\textquoteright}s disease.}, journal = {J Alzheimers Dis}, volume = {25}, year = {2011}, month = {2011}, pages = {93-102}, abstract = {

The heat shock protein (HSP) 70 family has been implicated in the pathology of Alzheimer{\textquoteright}s disease (AD). In this study, we examined common genetic variations in the 80 genes encoding HSP70 and its co-chaperones. We conducted a study in a series of 462 patients and 5238 unaffected participants derived from the Rotterdam Study, a population-based study including 7983 persons aged 55 years and older. We genotyped a total of 12,053 Single Nucleotide Polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. Replication was performed in two independent cohort studies, the Framingham Heart study (FHS; n = 806) and Cardiovascular Health Study (CHS; n = 2150). When adjusting for multiple testing, we found a small but consistent, though not significant effect of rs12118313 located 32 kb from PFDN2, with an OR of 1.19 (p-value from meta-analysis = 0.003). However this SNP was in the intron of another gene, suggesting it is unlikely this SNP reflects the effect of PFDN2. In a formal pathway analysis we found nominally significant evidence for an association of BAG, DNAJA and prefoldin with AD. These findings corroborate with those of a study of 2032 AD patients and 5328 controls, in which several members of the prefoldin family showed evidence for association to AD. Our study did not reveal evidence for a genetic variant if the HSP70 family with a major effect on AD. However, our findings of the single SNP analysis and pathway analysis suggest that multiple genetic variants in prefoldin are associated with AD.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Cohort Studies, Genetic Association Studies, Genetic Variation, HSP70 Heat-Shock Proteins, Humans, Middle Aged, Molecular Chaperones, Polymorphism, Single Nucleotide}, issn = {1875-8908}, doi = {10.3233/JAD-2011-101560}, author = {Broer, Linda and Ikram, Mohammad Arfan and Schuur, Maaike and DeStefano, Anita L and Bis, Joshua C and Liu, Fan and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Beiser, Alexa S and Longstreth, William T and Hofman, Albert and Aulchenko, Yurii and Seshadri, Sudha and Fitzpatrick, Annette L and Oostra, Ben A and Breteler, Monique M B and van Duijn, Cornelia M} } @article {1315, title = {Gender differences in tea, coffee, and cognitive decline in the elderly: the Cardiovascular Health Study.}, journal = {J Alzheimers Dis}, volume = {27}, year = {2011}, month = {2011}, pages = {553-66}, abstract = {

Although caffeine can enhance cognitive function acutely, long-term effects of consumption of caffeine-containing beverages such as tea and coffee are uncertain. Data on 4,809 participants aged 65 and older from the Cardiovascular Health Study (CHS) were used to examine the relationship of consumption of tea and coffee, assessed by food frequency questionnaire, on change in cognitive function by gender. Cognitive performance was assessed using serial Modified Mini-Mental State (3MS) examinations, which were administered annually up to 9 times. Linear mixed models were used to estimate rates of change in standard 3MS scores and scores modeled using item response theory (IRT). Models were adjusted for age, education, smoking status, clinic site, diabetes, hypertension, stroke, coronary heart disease, depression score, and APOE genotype. Over the median 7.9 years of follow-up, participants who did not consume tea or coffee declined annually an average of 1.30 points (women) and 1.11 points (men) on standard 3MS scores. In fully adjusted models using either standard or IRT 3MS scores, we found modestly reduced rates of cognitive decline for some, but not all, levels of coffee and tea consumption for women, with no consistent effect for men. Caffeine consumption was also associated with attenuation in cognitive decline in women. Dose-response relationships were not linear. These longitudinal analyses suggest a somewhat attenuated rate of cognitive decline among tea and coffee consumers compared to non-consumers in women but not in men. Whether this association is causal or due to unmeasured confounding requires further study.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Coffee, Cognition Disorders, Cohort Studies, Female, Follow-Up Studies, Humans, Longitudinal Studies, Male, Prospective Studies, Sex Characteristics, Tea}, issn = {1875-8908}, doi = {10.3233/JAD-2011-110431}, author = {Arab, Lenore and Biggs, Mary L and O{\textquoteright}Meara, Ellen S and Longstreth, W T and Crane, Paul K and Fitzpatrick, Annette L} } @article {1265, title = {Leukocyte telomere length and mortality in the Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {66}, year = {2011}, month = {2011 Apr}, pages = {421-9}, abstract = {

BACKGROUND: Leukocyte telomere length (LTL) is related to diseases of aging, but studies of mortality have been inconsistent.

METHODS: We evaluated LTL in relation to total mortality and specific cause of death in 1,136 participants of the Cardiovascular Health Study who provided blood samples in 1992-1993 and survived through 1997-1998. LTL was measured by Southern blots of the terminal restriction fragments. Cause of death was classified by a committee of physicians reviewing death certificates, medical records, and informant interviews.

RESULTS: A total of 468 (41.2\%) deaths occurred over 6.1 years of follow-up in participants with mean age of 73.9 years (SD 4.7), 65.4\% female, and 14.8\% African American. Although increased age and male gender were associated with shorter LTLs, African Americans had significantly longer LTLs independent of age and sex (p < .001). Adjusted for age, sex, and race, persons with the shortest quartile of LTL were 60\% more likely to die during follow-up than those within the longest quartile (hazard ratio: 1.61, 95\% confidence interval: 1.22-2.12, p = .001). The association remained after adjustment for cardiovascular disease risk factors. Evaluations of cause of death found LTL to be related to deaths due to an infectious disease etiology (hazard ratio: 2.80, 95\% confidence interval: 1.32-5.94, p = .007), whereas a borderline association was found for cardiac deaths (hazard ratio: 1.82, 95\% confidence interval: 0.95-3.49, p = .07) in adjusted models. Risk estimates for deaths due to cancer, dementia, and ischemic stroke were not significant.

CONCLUSION: These data weakly corroborate prior findings of associations between LTL and mortality in the elderly.

}, keywords = {Aged, Aged, 80 and over, Aging, Body Mass Index, Cardiovascular Diseases, Cause of Death, Comorbidity, Coronary Disease, Diabetes Mellitus, Female, Humans, Hypertension, Leukocytes, Longitudinal Studies, Male, Prospective Studies, Smoking, Stroke, Telomere}, issn = {1758-535X}, doi = {10.1093/gerona/glq224}, author = {Fitzpatrick, Annette L and Kronmal, Richard A and Kimura, Masayuki and Gardner, Jeffrey P and Psaty, Bruce M and Jenny, Nancy S and Tracy, Russell P and Hardikar, Sheetal and Aviv, Abraham} } @article {1398, title = {Comparing years of healthy life, measured in 16 ways, for normal weight and overweight older adults.}, journal = {J Obes}, volume = {2012}, year = {2012}, month = {2012}, pages = {894894}, abstract = {

Introduction. The traditional definitions of overweight and obesity are not age specific, even though the relationship of weight to mortality is different for older adults. Effects of adiposity on aspects of health beside mortality have not been well investigated. Methods. We calculated the number of years of healthy life (YHL) in the 10 years after baseline, for 5,747 older adults. YHL was defined in 16 different ways. We compared Normal and Overweight persons, classified either by body mass index (BMI) or by waist circumference (WC). Findings. YHL for Normal and Overweight persons differed significantly in 25\% of the comparisons, of which half favored the Overweight. Measures of physical health favored Normal weight, while measures of mental health and quality of life favored Overweight. Overweight was less favorable when defined by WC than by BMI. Obese persons usually had worse outcomes. Discussion. Overweight older adults averaged as many years of life and years of healthy life as those of Normal weight. There may be no outcome based reason to distinguish Normal from Overweight for older adults. Conclusion. The "Overweight paradox" appears to hold for nonmortality outcomes. New adiposity standards are needed for older adults, possibly different by race and sex.

}, issn = {2090-0716}, doi = {10.1155/2012/894894}, author = {Diehr, Paula and Thielke, Stephen and O{\textquoteright}Meara, Ellen and Fitzpatrick, Annette L and Newman, Anne} } @article {6090, title = {Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans.}, journal = {Hum Mol Genet}, volume = {21}, year = {2012}, month = {2012 Dec 15}, pages = {5385-94}, abstract = {

Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 {\texttimes} 10(-11)) and with the telomerase RNA component TERC (rs1317082, P = 1.1 {\texttimes} 10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 {\texttimes} 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 {\texttimes} 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.

}, keywords = {Genome-Wide Association Study, Humans, Kruppel-Like Transcription Factors, Telomere, Telomere Homeostasis, Telomere-Binding Proteins}, issn = {1460-2083}, doi = {10.1093/hmg/dds382}, author = {Mangino, Massimo and Hwang, Shih-Jen and Spector, Timothy D and Hunt, Steven C and Kimura, Masayuki and Fitzpatrick, Annette L and Christiansen, Lene and Petersen, Inge and Elbers, Clara C and Harris, Tamara and Chen, Wei and Srinivasan, Sathanur R and Kark, Jeremy D and Benetos, Athanase and El Shamieh, Said and Visvikis-Siest, Sophie and Christensen, Kaare and Berenson, Gerald S and Valdes, Ana M and Vi{\~n}uela, Ana and Garcia, Melissa and Arnett, Donna K and Broeckel, Ulrich and Province, Michael A and Pankow, James S and Kammerer, Candace and Liu, Yongmei and Nalls, Michael and Tishkoff, Sarah and Thomas, Fridtjof and Ziv, Elad and Psaty, Bruce M and Bis, Joshua C and Rotter, Jerome I and Taylor, Kent D and Smith, Erin and Schork, Nicholas J and Levy, Daniel and Aviv, Abraham} } @article {1328, title = {Leukocyte telomere length is associated with noninvasively measured age-related disease: The Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {67}, year = {2012}, month = {2012 Apr}, pages = {409-16}, abstract = {

BACKGROUND: Most studies of leukocyte telomere length (LTL) focus on diagnosed disease in one system. A more encompassing depiction of health is disease burden, defined here as the sum of noninvasively measured markers of structure or function in different organ systems. We determined if (a) shorter LTL is associated with greater age-related disease burden and (b) shorter LTL is less strongly associated with disease in individual systems or diagnosed chronic conditions (cardiovascular disease, stroke, pulmonary disease, diabetes, kidney disease, arthritis, or depression).

METHODS: LTL was measured by Southern blots of terminal restriction fragment length. Age-related disease was measured noninvasively and included carotid intima-media thickness, lung vital capacity, white matter grade, cystatin-C, and fasting glucose; each graded 0 (best tertile), 1 (middle tertile), or 2 (worst tertile) and summed (0 to 10) to estimate disease burden. Of 419 participants randomly selected for LTL measurement, 236 had disease burden assessed (mean [SD] age 74.2 [4.9] years, 42.4\% male, 86.8\% white, and 13.2\% black).

RESULTS: Mean (SD) LTL was 6,312 (615) bp, and disease score was 4.7 (2.1) points. An SD higher disease score (β [SE] = -132 [47] bp, p < .01), age (β [SE] = -107 [46], p = .02) or carotid thickness (β [SE] = -95 [40] bp, p = .02) was associated with shorter LTL, but diagnosed conditions or number of conditions were not associated with LTL. Disease score attenuated the effect of age on LTL by 35\%.

CONCLUSION: LTL was associated with a characterization of age-related disease burden across multiple physiologic systems, which was comparable to, but independent of, its association with age.

}, keywords = {African Americans, Aged, Aged, 80 and over, Cardiovascular Diseases, Carotid Intima-Media Thickness, Chronic Disease, Cystatin C, European Continental Ancestry Group, Female, Humans, Leukocytes, Lung, Male, Middle Aged, Telomere Homeostasis}, issn = {1758-535X}, doi = {10.1093/gerona/glr173}, author = {Sanders, Jason L and Fitzpatrick, Annette L and Boudreau, Robert M and Arnold, Alice M and Aviv, Abraham and Kimura, Masayuki and Fried, Linda F and Harris, Tamara B and Newman, Anne B} } @article {1375, title = {Telomere-associated polymorphisms correlate with cardiovascular disease mortality in Caucasian women: the Cardiovascular Health Study.}, journal = {Mech Ageing Dev}, volume = {133}, year = {2012}, month = {2012 May}, pages = {275-81}, abstract = {

Leukocyte telomere length (LTL) is linked to cardiovascular disease (CVD); however, it is unclear if LTL has an etiologic role in CVD. To gain insight into the LTL and CVD relationship, a cohort study of CVD mortality and single nucleotide polymorphisms (SNPs) in OBFC1 and TERC, genes related to LTL, was conducted among 3271 Caucasian participants ages >=65 years enrolled 1989-1990 in the Cardiovascular Health Study. Leukocyte DNA was genotyped for SNPs in OBFC1 (rs4387287 and rs9419958) and TERC (rs3772190) that were previously associated with LTL through genome-wide association studies. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95\% confidence intervals (CIs). The OBFC1 SNPs were in linkage disequilibrium (r(2)=0.99), and both SNPs were similarly associated with CVD mortality in women. For women, there was a decreased risk of CVD death associated with the minor allele (rs4387287), HR=0.7; 95\% CI: 0.5-0.9 (CC vs. AC) and HR=0.5; 95\% CI: 0.20-1.4 (CC vs. AA) (P-trend <0.01). For men there was no association, HR=1.0; 95\% CI: 0.7-1.3 (CC vs. AC) and HR=1.7; 95\% CI: 0.8-3.6 (CC vs. AA) (P-trend=0.64). These findings support the hypothesis that telomere biology and associated genes may play a role in CVD-related death, particularly among women.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cohort Studies, European Continental Ancestry Group, Female, Humans, Leukocytes, Male, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Risk, RNA, Sex Factors, Telomerase, Telomere}, issn = {1872-6216}, doi = {10.1016/j.mad.2012.03.002}, author = {Burnett-Hartman, Andrea N and Fitzpatrick, Annette L and Kronmal, Richard A and Psaty, Bruce M and Jenny, Nancy S and Bis, Josh C and Tracy, Russ P and Kimura, Masayuki and Aviv, Abraham} } @article {6002, title = {Atrial fibrillation and cognitive decline: a longitudinal cohort study.}, journal = {Neurology}, volume = {81}, year = {2013}, month = {2013 Jul 09}, pages = {119-25}, abstract = {

OBJECTIVE: We sought to determine whether in the absence of clinical stroke, people with atrial fibrillation experience faster cognitive decline than people without atrial fibrillation.

METHODS: We conducted a longitudinal analysis in the Cardiovascular Health Study, a community-based study of 5,888 men and women aged 65 years and older, enrolled in 1989/1990 or 1992/1993. Participants did not have atrial fibrillation or a history of stroke at baseline. Participants were censored when they experienced incident clinical stroke. Incident atrial fibrillation was identified by hospital discharge diagnosis codes and annual study ECGs. The main outcome was rate of decline in mean scores on the 100-point Modified Mini-Mental State Examination (3MSE), administered annually up to 9 times.

RESULTS: Analyses included 5,150 participants, of whom 552 (10.7\%) developed incident atrial fibrillation during a mean of 7 years of follow-up. Mean 3MSE scores declined faster after incident atrial fibrillation compared with no prior atrial fibrillation. For example, the predicted 5-year decline in mean 3MSE score from age 80 to age 85 was -6.4 points (95\% confidence interval [CI]: -7.0, -5.9) for participants without a history of atrial fibrillation, but was -10.3 points (95\% CI: -11.8, -8.9) for participants experiencing incident atrial fibrillation at age 80, a 5-year difference of -3.9 points (95\% CI: -5.3, -2.5).

CONCLUSIONS: In the absence of clinical stroke, people with incident atrial fibrillation are likely to reach thresholds of cognitive impairment or dementia at earlier ages than people with no history of atrial fibrillation.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Atrial Fibrillation, Cognition Disorders, Comorbidity, Female, Humans, Incidence, Longitudinal Studies, Luria-Nebraska Neuropsychological Battery, Male, Predictive Value of Tests}, issn = {1526-632X}, doi = {10.1212/WNL.0b013e31829a33d1}, author = {Thacker, Evan L and McKnight, Barbara and Psaty, Bruce M and Longstreth, W T and Sitlani, Colleen M and Dublin, Sascha and Arnold, Alice M and Fitzpatrick, Annette L and Gottesman, Rebecca F and Heckbert, Susan R} } @article {7628, title = {Use of antihypertensive medications and breast cancer risk.}, journal = {Cancer Causes Control}, volume = {24}, year = {2013}, month = {2013 Feb}, pages = {365-71}, abstract = {

PURPOSE: Use of specific antihypertensive medications (AHTs) has been hypothesized to increase breast cancer risk, but results across published studies are inconsistent.

METHODS: We re-evaluated the relationship between AHT use and breast cancer risk in a prospective cohort of 3,201 women >=65 years of age at recruitment now with more than double the length of follow-up (12 vs. 5 years) and substantially more breast cancer diagnoses (188 compared with 75 cases). We estimated the association between AHT use overall as well as use of specific formulations (based on data collected annually) and breast cancer risk using multivariate-adjusted Cox regression.

RESULTS: Compared with women who reported no use of AHTs, women who had used calcium channel blockers (CCB) within the past two years had a 1.6-fold increased risk of breast cancer (95 \% confidence interval (CI): 1.0-2.5), and in particular, recent users of immediate-release CCBs had a 2.4-fold increased risk (95 \% CI: 1.3-4.5). Neither ever nor recent use of any other type of AHT was associated with breast cancer risk.

CONCLUSIONS: While the observed association between immediate-release CCBs and breast cancer risk is based on a small sample size and needs to be interpreted cautiously, this result is consistent with others in the literature. However, given declines in use of these preparations in favor of sustained-release CCBs, which was not related to risk, the potential clinical and public health impact of this association is limited. This study also adds to the evidence that other commonly used AHTs are not strongly related to breast cancer risk.

}, keywords = {Aged, Aged, 80 and over, Antihypertensive Agents, Breast Neoplasms, Cohort Studies, Female, Humans, Proportional Hazards Models, Prospective Studies, Risk Factors, United States}, issn = {1573-7225}, doi = {10.1007/s10552-012-0122-8}, author = {Saltzman, Babette S and Weiss, Noel S and Sieh, Weiva and Fitzpatrick, Annette L and McTiernan, Anne and Daling, Janet R and Li, Christopher I} } @article {6541, title = {Fibrosis-related biomarkers and incident cardiovascular disease in older adults: the cardiovascular health study.}, journal = {Circ Arrhythm Electrophysiol}, volume = {7}, year = {2014}, month = {2014 Aug}, pages = {583-9}, abstract = {

BACKGROUND: Fibrotic changes in the heart and arteries have been implicated in a diverse range of cardiovascular diseases (CVD), but whether circulating biomarkers that reflect fibrosis are associated with CVD is unknown.

METHODS AND RESULTS: We determined the associations of 2 biomarkers of fibrosis, transforming growth factor- β (TGF-β), and procollagen type III N-terminal propeptide (PIIINP), with incident heart failure, myocardial infarction, and stroke among community-living older adults in the Cardiovascular Health Study. We measured circulating TGF-β (n=1371) and PIIINP (n=2568) from plasma samples collected in 1996 and ascertained events through 2010. Given TGF-β{\textquoteright}s pleiotropic effects on inflammation and fibrogenesis, we investigated potential effect modification by C-reactive protein in secondary analyses. After adjustment for sociodemographic, clinical, and biochemical risk factors, PIIINP was associated with total CVD (hazard ratio [HR] per SD=1.07; 95\% confidence interval [CI], 1.01-1.14) and heart failure (HR per SD=1.08; CI, 1.01-1.16) but not myocardial infarction or stroke. TGF-β was not associated with any CVD outcomes in the full cohort but was associated with total CVD (HR per SD=1.16; CI, 1.02-1.31), heart failure (HR per SD=1.16; CI, 1.01-1.34), and stroke (HR per SD=1.20; CI, 1.01-1.42) among individuals with C-reactive protein above the median, 2.3 mg/L (P interaction <0.05).

CONCLUSIONS: Our findings provide large-scale, prospective evidence that circulating biomarkers of fibrosis, measured in community-living individuals late in life, are associated with CVD. Further research on whether TGF-β has a stronger fibrogenic effect in the setting of inflammation is warranted.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Female, Fibrosis, Heart Failure, Humans, Incidence, Male, Myocardial Infarction, Peptide Fragments, Procollagen, Prognosis, Prospective Studies, Risk Assessment, Risk Factors, Stroke, Time Factors, Transforming Growth Factor beta, United States}, issn = {1941-3084}, doi = {10.1161/CIRCEP.114.001610}, author = {Agarwal, Isha and Glazer, Nicole L and Barasch, Eddy and Biggs, Mary L and Djouss{\'e}, Luc and Fitzpatrick, Annette L and Gottdiener, John S and Ix, Joachim H and Kizer, Jorge R and Rimm, Eric B and Sicovick, David S and Tracy, Russell P and Mukamal, Kenneth J} } @article {6336, title = {Fibrosis-related biomarkers and risk of total and cause-specific mortality: the cardiovascular health study.}, journal = {Am J Epidemiol}, volume = {179}, year = {2014}, month = {2014 Jun 01}, pages = {1331-9}, abstract = {

Fibrosis has been implicated in diverse diseases of the liver, kidney, lungs, and heart, but its importance as a risk factor for mortality remains unconfirmed. We determined the prospective associations of 2 complementary biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with total and cause-specific mortality risks among community-living older adults in the Cardiovascular Health Study (1996-2010). We measured circulating TGF-β and PIIINP levels in plasma samples collected in 1996 and ascertained the number of deaths through 2010. Both TGF-β and PIIINP were associated with elevated risks of total and pulmonary mortality after adjustment for sociodemographic, clinical, and biochemical risk factors. For total mortality, the hazard ratios per doubling of TGF-β and PIIINP were 1.09 (95\% confidence interval (CI): 1.01, 1.17; P = 0.02) and 1.14 (CI: 1.03, 1.27; P = 0.01), respectively. The corresponding hazard ratios for pulmonary mortality were 1.27 (CI: 1.01, 1.60; P = 0.04) for TGF-β and 1.52 (CI: 1.11, 2.10; P = 0.01) for PIIINP. Associations of TGF-β and PIIINP with total and pulmonary mortality were strongest among individuals with higher C-reactive protein concentrations (P for interaction < 0.05). Our findings provide some of the first large-scale prospective evidence that circulating biomarkers of fibrosis measured late in life are associated with death.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cause of Death, Female, Fibrosis, Follow-Up Studies, Humans, Likelihood Functions, Male, Multivariate Analysis, Peptide Fragments, Procollagen, Proportional Hazards Models, Prospective Studies, Risk Factors, Transforming Growth Factor beta}, issn = {1476-6256}, doi = {10.1093/aje/kwu067}, author = {Agarwal, Isha and Glazer, Nicole L and Barasch, Eddy and Biggs, Mary L and Djouss{\'e}, Luc and Fitzpatrick, Annette L and Gottdiener, John S and Ix, Joachim H and Kizer, Jorge R and Rimm, Eric B and Siscovick, David S and Tracy, Russell P and Zieman, Susan J and Mukamal, Kenneth J} } @article {6617, title = {Gene-wide analysis detects two new susceptibility genes for Alzheimer{\textquoteright}s disease.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e94661}, abstract = {

BACKGROUND: Alzheimer{\textquoteright}s disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer{\textquoteright}s Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer{\textquoteright}s cases and 48,466 controls.

PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4{\texttimes}10-6) and 14 (IGHV1-67 p = 7.9{\texttimes}10-8) which indexed novel susceptibility loci.

SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer{\textquoteright}s disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer{\textquoteright}s disease.

}, keywords = {Alzheimer Disease, Carrier Proteins, Case-Control Studies, Genome-Wide Association Study, Heat-Shock Proteins, Humans, Polymorphism, Single Nucleotide, Receptors, Antigen, B-Cell}, issn = {1932-6203}, doi = {10.1371/journal.pone.0094661}, author = {Escott-Price, Valentina and Bellenguez, C{\'e}line and Wang, Li-San and Choi, Seung-Hoan and Harold, Denise and Jones, Lesley and Holmans, Peter and Gerrish, Amy and Vedernikov, Alexey and Richards, Alexander and DeStefano, Anita L and Lambert, Jean-Charles and Ibrahim-Verbaas, Carla A and Naj, Adam C and Sims, Rebecca and Jun, Gyungah and Bis, Joshua C and Beecham, Gary W and Grenier-Boley, Benjamin and Russo, Giancarlo and Thornton-Wells, Tricia A and Denning, Nicola and Smith, Albert V and Chouraki, Vincent and Thomas, Charlene and Ikram, M Arfan and Zelenika, Diana and Vardarajan, Badri N and Kamatani, Yoichiro and Lin, Chiao-Feng and Schmidt, Helena and Kunkle, Brian and Dunstan, Melanie L and Vronskaya, Maria and Johnson, Andrew D and Ruiz, Agustin and Bihoreau, Marie-Th{\'e}r{\`e}se and Reitz, Christiane and Pasquier, Florence and Hollingworth, Paul and Hanon, Olivier and Fitzpatrick, Annette L and Buxbaum, Joseph D and Campion, Dominique and Crane, Paul K and Baldwin, Clinton and Becker, Tim and Gudnason, Vilmundur and Cruchaga, Carlos and Craig, David and Amin, Najaf and Berr, Claudine and Lopez, Oscar L and De Jager, Philip L and Deramecourt, Vincent and Johnston, Janet A and Evans, Denis and Lovestone, Simon and Letenneur, Luc and Hernandez, Isabel and Rubinsztein, David C and Eiriksdottir, Gudny and Sleegers, Kristel and Goate, Alison M and Fi{\'e}vet, Nathalie and Huentelman, Matthew J and Gill, Michael and Brown, Kristelle and Kamboh, M Ilyas and Keller, Lina and Barberger-Gateau, Pascale and McGuinness, Bernadette and Larson, Eric B and Myers, Amanda J and Dufouil, Carole and Todd, Stephen and Wallon, David and Love, Seth and Rogaeva, Ekaterina and Gallacher, John and George-Hyslop, Peter St and Clarimon, Jordi and Lleo, Alberto and Bayer, Anthony and Tsuang, Debby W and Yu, Lei and Tsolaki, Magda and Boss{\`u}, Paola and Spalletta, Gianfranco and Proitsi, Petra and Collinge, John and Sorbi, Sandro and Garcia, Florentino Sanchez and Fox, Nick C and Hardy, John and Naranjo, Maria Candida Deniz and Bosco, Paolo and Clarke, Robert and Brayne, Carol and Galimberti, Daniela and Scarpini, Elio and Bonuccelli, Ubaldo and Mancuso, Michelangelo and Siciliano, Gabriele and Moebus, Susanne and Mecocci, Patrizia and Zompo, Maria Del and Maier, Wolfgang and Hampel, Harald and Pilotto, Alberto and Frank-Garc{\'\i}a, Ana and Panza, Francesco and Solfrizzi, Vincenzo and Caffarra, Paolo and Nacmias, Benedetta and Perry, William and Mayhaus, Manuel and Lannfelt, Lars and Hakonarson, Hakon and Pichler, Sabrina and Carrasquillo, Minerva M and Ingelsson, Martin and Beekly, Duane and Alvarez, Victoria and Zou, Fanggeng and Valladares, Otto and Younkin, Steven G and Coto, Eliecer and Hamilton-Nelson, Kara L and Gu, Wei and Razquin, Cristina and Pastor, Pau and Mateo, Ignacio and Owen, Michael J and Faber, Kelley M and Jonsson, Palmi V and Combarros, Onofre and O{\textquoteright}Donovan, Michael C and Cantwell, Laura B and Soininen, Hilkka and Blacker, Deborah and Mead, Simon and Mosley, Thomas H and Bennett, David A and Harris, Tamara B and Fratiglioni, Laura and Holmes, Clive and de Bruijn, Renee F A G and Passmore, Peter and Montine, Thomas J and Bettens, Karolien and Rotter, Jerome I and Brice, Alexis and Morgan, Kevin and Foroud, Tatiana M and Kukull, Walter A and Hannequin, Didier and Powell, John F and Nalls, Michael A and Ritchie, Karen and Lunetta, Kathryn L and Kauwe, John S K and Boerwinkle, Eric and Riemenschneider, Matthias and Boada, Merce and Hiltunen, Mikko and Martin, Eden R and Schmidt, Reinhold and Rujescu, Dan and Dartigues, Jean-Fran{\c c}ois and Mayeux, Richard and Tzourio, Christophe and Hofman, Albert and N{\"o}then, Markus M and Graff, Caroline and Psaty, Bruce M and Haines, Jonathan L and Lathrop, Mark and Pericak-Vance, Margaret A and Launer, Lenore J and Van Broeckhoven, Christine and Farrer, Lindsay A and van Duijn, Cornelia M and Ramirez, Alfredo and Seshadri, Sudha and Schellenberg, Gerard D and Amouyel, Philippe and Williams, Julie} } @article {6364, title = {Kidney function and cognitive health in older adults: the Cardiovascular Health Study.}, journal = {Am J Epidemiol}, volume = {180}, year = {2014}, month = {2014 Jul 01}, pages = {68-75}, abstract = {

Recent evidence has demonstrated the importance of kidney function in healthy aging. We examined the association between kidney function and change in cognitive function in 3,907 participants in the Cardiovascular Health Study who were recruited from 4 US communities and studied from 1992 to 1999. Kidney function was measured by cystatin C-based estimated glomerular filtration rate (eGFRcys). Cognitive function was assessed using the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test, which were administered up to 7 times during annual visits. There was an association between eGFRcys and change in cognitive function after adjustment for confounders; persons with an eGFRcys of less than 60 mL/minute/1.73 m(2) had a 0.64 (95\% confidence interval: 0.51, 0.77) points/year faster decline in Modified Mini-Mental State Examination score and a 0.42 (95\% confidence interval: 0.28, 0.56) points/year faster decline in Digit Symbol Substitution Test score compared with persons with an eGFRcys of 90 or more mL/minute/1.73 m(2). Additional adjustment for intermediate cardiovascular events modestly affected these associations. Participants with an eGFRcys of less than 60 mL/minute/1.73 m(2) had fewer cognitive impairment-free life-years on average compared with those with eGFRcys of 90 or more mL/minute/1.73 m(2), independent of confounders and mediating cardiovascular events (mean difference = -0.44, 95\% confidence interval: -0.62, -0.26). Older adults with lower kidney function are at higher risk of worsening cognitive function.

}, keywords = {Aged, Cardiovascular Diseases, Cognition, Cognition Disorders, Cystatin C, Female, Glomerular Filtration Rate, Health Status, Humans, Kidney, Kidney Diseases, Male, Neuropsychological Tests}, issn = {1476-6256}, doi = {10.1093/aje/kwu102}, author = {Darsie, Brendan and Shlipak, Michael G and Sarnak, Mark J and Katz, Ronit and Fitzpatrick, Annette L and Odden, Michelle C} } @article {6293, title = {Leukocyte telomere length and age at menopause.}, journal = {Epidemiology}, volume = {25}, year = {2014}, month = {2014 Jan}, pages = {139-46}, abstract = {

BACKGROUND: Telomere length is a marker of cellular aging that varies with the individual, is inherited, and is highly correlated across somatic cell types within persons. Interindividual variability of telomere length may partly explain differences in reproductive aging rates. We examined whether leukocyte telomere length was associated with menopausal age.

METHODS: We evaluated the relationship between leukocyte telomere length and age at natural menopause in 486 white women >=65 years of age. We fit linear regression models adjusted for age, income, education, body mass index, physical activity, smoking, and alcohol intake. We repeated the analysis in women with surgical menopause. We also performed sensitivity analyses excluding women (1) with unilateral oophorectomy, (2) who were nulliparous, or (3) reporting menopausal age <40 years, among other exclusions.

RESULTS: For every 1-kb increase in leukocyte telomere length, average age at natural menopause increased by 10.2 months (95\% confidence interval = 1.3 to 19.0). There was no association among 179 women reporting surgical menopause. In all but one sensitivity analysis, the association between leukocyte telomere length and age at menopause became stronger. However, when excluding women with menopausal age <40 years, the association decreased to 7.5 months (-0.4 to 15.5).

CONCLUSIONS: Women with the longest leukocyte telomere length underwent menopause 3 years later than those with the shortest leukocyte telomere length. If an artifact, an association would likely also have been observed in women with surgical menopause. If these results are replicated, leukocyte telomere length may prove to be a useful predictor of age at menopause.

}, keywords = {Adult, Age of Onset, Aged, Aging, Alcohol Drinking, Body Mass Index, Educational Status, European Continental Ancestry Group, Female, Humans, Leukocytes, Linear Models, Menopause, Middle Aged, Motor Activity, Smoking, Telomere}, issn = {1531-5487}, doi = {10.1097/EDE.0000000000000017}, author = {Gray, Kristen E and Schiff, Melissa A and Fitzpatrick, Annette L and Kimura, Masayuki and Aviv, Abraham and Starr, Jacqueline R} } @article {6380, title = {Lipoprotein-associated phospholipase A2 and risk of dementia in the Cardiovascular Health Study.}, journal = {Atherosclerosis}, volume = {235}, year = {2014}, month = {2014 Aug}, pages = {384-91}, abstract = {

OBJECTIVE: To evaluate associations between Lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity with risk of dementia and its subtypes.

METHODS: Analysis were completed on 3320 participants of the Cardiovascular Health Study (CHS), a population-based longitudinal study of community-dwelling adults age >=65 years followed for an average of 5.4 years. Baseline serum Lp-PLA2 mass was measured using a sandwich enzyme immunoassay and Lp-PLA2 activity utilized a tritiated-platelet activating factor activity assay. Cox proportional hazards regression assessed the relative risk of incident dementia with higher baseline Lp-PLA2 adjusting for demographics, cardiovascular disease (CVD) and risk factors, inflammation markers and apolipoprotein E (APOE) genotype.

RESULTS: Each standard deviation higher Lp-PLA2 mass and activity were related to increased risk of dementia (fully adjusted HR: 1.11 per SD, 95\% CI: 1.00-1.24 for mass; HR: 1.12 per SD, 95\% CI: 1.00-1.26 for activity). Persons in the highest quartile of Lp-PLA2 mass were 50\% more likely to develop dementia than those in the lowest quartile in adjusted models (HR: 1.49; 95\% CI: 1.08-2.06). Among dementia subtypes, the risk of AD was increased two-fold in the highest compared to lowest quartile of Lp-PLA2 mass (adjusted HR: 1.98, 95\% CI: 1.22-3.21). Results were attenuated in models of mixed dementia and VaD. Lp-PLA2 activity also doubled the risk of mixed dementia in the highest compared to lowest quartile (HR: 2.21, 95\% CI: 1.12-4.373).

INTERPRETATION: These data support Lp-PLA2 as a risk factor for dementia independent of CVD and its risk factors. Further study is required to clarify the role of Lp-PLA2-related mechanisms in dementia subtypes.

}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, Aged, Alzheimer Disease, Dementia, Female, Humans, Male, Risk, Risk Factors}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2014.04.032}, author = {Fitzpatrick, Annette L and Irizarry, Michael C and Cushman, Mary and Jenny, Nancy S and Chi, Gloria C and Koro, Carol} } @article {6625, title = {Ratio of urine albumin to creatinine attenuates the association of dementia with hip fracture risk.}, journal = {J Clin Endocrinol Metab}, volume = {99}, year = {2014}, month = {2014 Nov}, pages = {4116-23}, abstract = {

CONTEXT: Microvascular disease is a leading cause of cognitive impairment. Approximately 50\% of people with a hip fracture have cognitive impairment.

OBJECTIVE: We tested the hypothesis that microvascular diseases of the brain (lacunar infarcts and white matter disease [WMD]), kidney (albuminuria [>= 30 mg/g creatinine] and albumin creatinine ratio [ACR]), and eye (retinal vascular disorders) attenuate the association of cognitive impairment with hip fracture risk.

SETTING: The Cardiovascular Health Cognition Study.

PATIENTS: Three thousand, one-hundred six participants (mean age, \~{} 79 y; 8.84 y median follow-up) with cognitive testing. Subsets received ACR testing (n=2389), brain magnetic resonance imaging scans (n = 2094), and retinal photography (n = 1098).

MAIN OUTCOME MEASURE: Incident hip fracture.

RESULTS: There were 488 participants (16\%) with mild cognitive impairment (MCI) and 564 (18\%) with dementia. There were 337 incident hip fractures, of which 19\% occurred in participants with MCI and 26\% in participants with dementia. Adjusted hazard ratios (HR) and 95\% confidence interval for hip fracture in participants with MCI were 2.45 (1.67-3.61) and for dementia 2.35 (1.57-3.52). With doubling of ACR, the HR for fracture was attenuated in participants with dementia compared with participants with normal cognition [interaction HR 0.70 (0.55-0.91)]. No such effect was found in participants with MCI. Albuminuria, lacunar infarcts, WMD, and retinal vascular disease (RVD) did not modify the association of dementia or MCI with hip fracture risk.

CONCLUSIONS: ACR attenuates part of the risk of hip fracture in people with dementia, suggesting that these disorders share a common pathogenesis.

}, keywords = {Aged, Aged, 80 and over, Albuminuria, Creatinine, Dementia, Female, Hip Fractures, Humans, Incidence, Magnetic Resonance Imaging, Male, Mild Cognitive Impairment, Neuropsychological Tests, Prospective Studies, Risk}, issn = {1945-7197}, doi = {10.1210/jc.2014-2409}, author = {B{\r u}zkov{\'a}, Petra and Barzilay, Joshua I and Fink, Howard A and Robbins, John A and Cauley, Jane A and Fitzpatrick, Annette L} } @article {6594, title = {Telomere length and the risk of atrial fibrillation: insights into the role of biological versus chronological aging.}, journal = {Circ Arrhythm Electrophysiol}, volume = {7}, year = {2014}, month = {2014 Dec}, pages = {1026-32}, abstract = {

BACKGROUND: Advanced age is the most important risk factor for atrial fibrillation (AF); however, the mechanism remains unknown. Telomeres, regions of DNA that shorten with cell division, are considered reliable markers of biological aging. We sought to examine the association between leukocyte telomere length (LTL) and incident AF in a large population-based cohort using direct LTL measurements and genetic data. To further explore our findings, we compared atrial cell telomere length and LTL in cardiac surgery patients.

METHODS AND RESULTS: Mean LTL and the TERT rs2736100 single nucleotide polymorphism were assessed as predictors of incident AF in the Cardiovascular Health Study (CHS). Among the surgical patients, within subject comparison of atrial cell telomere length versus LTL was assessed. Among 1639 CHS participants, we observed no relationship between mean LTL and incident AF before and after adjustment for potential confounders (adjusted hazard ratio, 1.09; 95\% confidence interval: 0.92-1.29; P=0.299); chronologic age remained strongly associated with AF in the same model. No association was observed between the TERT rs2736100 single nucleotide polymorphism and incident AF (adjusted hazard ratio: 0.95; 95\% confidence interval: 0.88-1.04; P=0.265). In 35 cardiac surgery patients (26 with AF), atrial cell telomere length was longer than LTL (1.19 {\textpm} 0.20 versus 1.02 {\textpm} 0.25 [T/S ratio], P<0.001), a finding that remained consistent within the AF subgroup.

CONCLUSIONS: Our study revealed no evidence of an association between LTL and incident AF and no evidence of relative atrial cell telomere shortening in AF. Chronological aging independent of biological markers of aging is the primary risk factor for AF.

}, keywords = {Age Factors, Aged, Aging, Atrial Fibrillation, California, Cardiac Surgical Procedures, Cellular Senescence, Cross-Sectional Studies, Female, Genetic Predisposition to Disease, Humans, Incidence, Leukocytes, Male, Phenotype, Polymorphism, Single Nucleotide, Prospective Studies, Risk Assessment, Risk Factors, Telomerase, Telomere, Time Factors}, issn = {1941-3084}, doi = {10.1161/CIRCEP.114.001781}, author = {Roberts, Jason D and Dewland, Thomas A and Longoria, James and Fitzpatrick, Annette L and Ziv, Elad and Hu, Donglei and Lin, Jue and Glidden, David V and Psaty, Bruce M and Burchard, Esteban G and Blackburn, Elizabeth H and Olgin, Jeffrey E and Heckbert, Susan R and Marcus, Gregory M} } @article {6817, title = {DCAF4, a novel gene associated with leucocyte telomere length.}, journal = {J Med Genet}, volume = {52}, year = {2015}, month = {2015 Mar}, pages = {157-62}, abstract = {

BACKGROUND: Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR).

RESULTS: Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4{\texttimes}10(-10)) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1{\texttimes}10(-3) and 2{\texttimes}10(-3), respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97{\texttimes}10(-169) to 3.42{\texttimes}10(-24).

CONCLUSIONS: We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.

}, keywords = {Alleles, Carrier Proteins, Gene Expression Regulation, Genome-Wide Association Study, Humans, Leukocytes, Melanoma, Risk Factors, Telomere, Telomere Homeostasis}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2014-102681}, author = {Mangino, Massimo and Christiansen, Lene and Stone, Rivka and Hunt, Steven C and Horvath, Kent and Eisenberg, Dan T A and Kimura, Masayuki and Petersen, Inge and Kark, Jeremy D and Herbig, Utz and Reiner, Alex P and Benetos, Athanase and Codd, Veryan and Nyholt, Dale R and Sinnreich, Ronit and Christensen, Kaare and Nassar, Hisham and Hwang, Shih-Jen and Levy, Daniel and Bataille, Veronique and Fitzpatrick, Annette L and Chen, Wei and Berenson, Gerald S and Samani, Nilesh J and Martin, Nicholas G and Tishkoff, Sarah and Schork, Nicholas J and Kyvik, Kirsten Ohm and Dalg{\r a}rd, Christine and Spector, Timothy D and Aviv, Abraham} } @article {6665, title = {Fibrosis-related biomarkers and large and small vessel disease: the Cardiovascular Health Study.}, journal = {Atherosclerosis}, volume = {239}, year = {2015}, month = {2015 Apr}, pages = {539-46}, abstract = {

OBJECTIVE: Fibrosis has been implicated in a number of pathological, organ-based conditions of the liver, kidney, heart, and lungs. The objective of this study was to determine whether biomarkers of fibrosis are associated with vascular disease in the large and/or small vessels.

METHODS: We evaluated the associations of two circulating biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with incident peripheral artery disease (PAD) and subclinical macrovascular (carotid intima-media thickness, flow-mediated vasodilation, ankle-brachial index, retinal vein diameter), and microvascular (retinal artery diameter and retinopathy) disease among older adults in the Cardiovascular Health Study. We measured TGF-β and PIIINP from samples collected in 1996 and ascertained clinical PAD through 2011. Measurements of large and small vessels were collected between 1996 and 1998.

RESULTS: After adjustment for sociodemographic, clinical, and biochemical risk factors, TGF-β was associated with incident PAD (hazard ratio [HR]~=~1.36 per doubling of TGF-β, 95\% confidence interval [CI]~=~1.04, 1.78) and retinal venular diameter (1.63~μm per doubling of TGF-β, CI~=~0.23, 3.02). PIIINP was not associated with incident PAD, but was associated with carotid intima-media thickness (0.102~mm per doubling of PIIINP, CI~=~0.029, 0.174) and impaired brachial artery reactivity (-0.20\% change per doubling of PIIINP, CI~=~-0.39,~-0.02). Neither TGF-β nor PIIINP were associated with retinal arteriolar diameter or retinopathy.

CONCLUSIONS: Serum concentrations of fibrosis-related biomarkers were associated with several measures of large vessel disease, including incident PAD, but not with small vessel disease. Fibrosis may contribute to large vessel atherosclerosis in older adults.

}, keywords = {Aged, Ankle Brachial Index, Biomarkers, Brachial Artery, Carotid Artery Diseases, Carotid Intima-Media Thickness, Cross-Sectional Studies, Female, Fibrosis, Humans, Incidence, Male, Peptide Fragments, Peripheral Arterial Disease, Predictive Value of Tests, Procollagen, Prognosis, Prospective Studies, Retinal Diseases, Risk Factors, Transforming Growth Factor beta, United States, Vasodilation}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2015.02.020}, author = {Agarwal, Isha and Arnold, Alice and Glazer, Nicole L and Barasch, Eddy and Djouss{\'e}, Luc and Fitzpatrick, Annette L and Gottdiener, John S and Ix, Joachim H and Jensen, Richard A and Kizer, Jorge R and Rimm, Eric B and Siscovick, David S and Tracy, Russell P and Wong, Tien Y and Mukamal, Kenneth J} } @article {6684, title = {Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.}, journal = {Biol Psychiatry}, volume = {77}, year = {2015}, month = {2015 Apr 15}, pages = {749-63}, abstract = {

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.

METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged >=45 years. Replication of suggestive associations (p < 5 {\texttimes} 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.

RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 {\texttimes} 10(-10)) and replication cohorts (p = 5.65 {\texttimes} 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 {\texttimes} 10(-8), and rs6813517 [SPOCK3], p = 2.58 {\texttimes} 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.

CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

}, keywords = {Aged, Aged, 80 and over, Aging, Apolipoproteins E, Claudin-5, Cohort Studies, Female, Genome-Wide Association Study, Genotype, Humans, Male, Memory Disorders, Middle Aged, Polymorphism, Single Nucleotide, Proteins, Proteoglycans, Regression Analysis, Sulfotransferases, Verbal Learning}, issn = {1873-2402}, doi = {10.1016/j.biopsych.2014.08.027}, author = {Debette, Stephanie and Ibrahim Verbaas, Carla A and Bressler, Jan and Schuur, Maaike and Smith, Albert and Bis, Joshua C and Davies, Gail and Wolf, Christiane and Gudnason, Vilmundur and Chibnik, Lori B and Yang, Qiong and DeStefano, Anita L and de Quervain, Dominique J F and Srikanth, Velandai and Lahti, Jari and Grabe, Hans J and Smith, Jennifer A and Priebe, Lutz and Yu, Lei and Karbalai, Nazanin and Hayward, Caroline and Wilson, James F and Campbell, Harry and Petrovic, Katja and Fornage, Myriam and Chauhan, Ganesh and Yeo, Robin and Boxall, Ruth and Becker, James and Stegle, Oliver and Mather, Karen A and Chouraki, Vincent and Sun, Qi and Rose, Lynda M and Resnick, Susan and Oldmeadow, Christopher and Kirin, Mirna and Wright, Alan F and Jonsdottir, Maria K and Au, Rhoda and Becker, Albert and Amin, Najaf and Nalls, Mike A and Turner, Stephen T and Kardia, Sharon L R and Oostra, Ben and Windham, Gwen and Coker, Laura H and Zhao, Wei and Knopman, David S and Heiss, Gerardo and Griswold, Michael E and Gottesman, Rebecca F and Vitart, Veronique and Hastie, Nicholas D and Zgaga, Lina and Rudan, Igor and Polasek, Ozren and Holliday, Elizabeth G and Schofield, Peter and Choi, Seung Hoan and Tanaka, Toshiko and An, Yang and Perry, Rodney T and Kennedy, Richard E and Sale, Mich{\`e}le M and Wang, Jing and Wadley, Virginia G and Liewald, David C and Ridker, Paul M and Gow, Alan J and Pattie, Alison and Starr, John M and Porteous, David and Liu, Xuan and Thomson, Russell and Armstrong, Nicola J and Eiriksdottir, Gudny and Assareh, Arezoo A and Kochan, Nicole A and Widen, Elisabeth and Palotie, Aarno and Hsieh, Yi-Chen and Eriksson, Johan G and Vogler, Christian and van Swieten, John C and Shulman, Joshua M and Beiser, Alexa and Rotter, Jerome and Schmidt, Carsten O and Hoffmann, Wolfgang and N{\"o}then, Markus M and Ferrucci, Luigi and Attia, John and Uitterlinden, Andr{\'e} G and Amouyel, Philippe and Dartigues, Jean-Fran{\c c}ois and Amieva, H{\'e}l{\`e}ne and R{\"a}ikk{\"o}nen, Katri and Garcia, Melissa and Wolf, Philip A and Hofman, Albert and Longstreth, W T and Psaty, Bruce M and Boerwinkle, Eric and DeJager, Philip L and Sachdev, Perminder S and Schmidt, Reinhold and Breteler, Monique M B and Teumer, Alexander and Lopez, Oscar L and Cichon, Sven and Chasman, Daniel I and Grodstein, Francine and M{\"u}ller-Myhsok, Bertram and Tzourio, Christophe and Papassotiropoulos, Andreas and Bennett, David A and Ikram, M Arfan and Deary, Ian J and van Duijn, Cornelia M and Launer, Lenore and Fitzpatrick, Annette L and Seshadri, Sudha and Mosley, Thomas H} } @article {6743, title = {Physical Activity, Physical Fitness, and Leukocyte Telomere Length: The Cardiovascular Health Study.}, journal = {Med Sci Sports Exerc}, volume = {47}, year = {2015}, month = {2015 Dec}, pages = {2525-34}, abstract = {

INTRODUCTION: The influence of physical activity (PA) and physical fitness (PF) at older ages on changes in telomere length (TL)--repetitive DNA sequences that may mark biologic aging--is not well-established. Few prior studies (mainly cross-sectional) have been conducted in older adults, and few studies have evaluated PF.

METHODS: We investigated cross-sectional and prospective associations of PA and PF with leukocyte TL among 582 older adults (mean {\textpm} SD age, 73 {\textpm} 5 yr at baseline) in the Cardiovascular Health Study, with serial TL measures and PA and PF assessed multiple times. Cross-sectional associations were assessed using multivariable repeated-measures regression, in which cumulatively averaged PA and PF measures were related to TL. Longitudinal analyses assessed cumulatively averaged PA and PF against later changes in TL, and changes in cumulatively averaged PA and PF against changes in TL.

RESULTS: Cross-sectionally, greater walking distance and chair test performance, but not other PA and PF measures, were each associated with longer TL (P trend = 0.007 and 0.04, respectively). In longitudinal analyses, no significant associations of baseline PA and PF with change in TL were observed. In contrast, changes in leisure-time activity and chair test performance were each inversely associated with changes in TL.

CONCLUSIONS: Cross-sectional analyses suggest that greater PA and PF are associated with longer TL. Prospective analyses show that changes in PA and PF are associated with differences in changes in TL. Even later in life, changes in certain PA and PF measures are associated with changes in TL, suggesting that leisure-time activity and fitness could reduce leukocyte telomere attrition among older adults.

}, keywords = {Aged, Aging, Cross-Sectional Studies, Exercise Test, Female, Hand Strength, Humans, Leukocytes, Male, Motor Activity, Physical Fitness, Prospective Studies, Telomere Homeostasis, Walking}, issn = {1530-0315}, doi = {10.1249/MSS.0000000000000720}, author = {Soares-Miranda, Luisa and Imamura, Fumiaki and Siscovick, David and Jenny, Nancy Swords and Fitzpatrick, Annette L and Mozaffarian, Dariush} } @article {7245, title = {Changes in Depressive Symptoms and Subsequent Risk of Stroke in the Cardiovascular Health Study.}, journal = {Stroke}, year = {2016}, month = {2016 Dec 06}, abstract = {

BACKGROUND AND PURPOSE: Depression is associated with stroke, but the effects of changes in depressive symptoms on stroke risk are not well understood. This study examined whether depressive symptom changes across 2 successive annual assessments were associated with incident stroke the following year.

METHODS: We used visit data from 4319 participants of the Cardiovascular Health Study who were stroke free at baseline to examine whether changes in depressive symptoms classified across 2 consecutive annual assessments predicted incident first stroke during the subsequent year. Depressive symptoms were assessed using the 10-item Center for Epidemiologic Studies Depression scale (high versus low at >=10). Survival models were inverse probability weighted to adjust for demographics, health behaviors, medical conditions, past depressive symptoms, censoring, and survival.

RESULTS: During follow-up, 334 strokes occurred. Relative to stable low scores of depressive symptoms, improved depression symptoms were associated with almost no excess risk of stroke (adjusted hazards ratio, 1.02; 95\% confidence interval, 0.66-1.58). New-onset symptoms were nonsignificantly associated with elevated stroke risk (adjusted hazards ratio, 1.44; 95\% confidence interval, 0.97-2.14), whereas persistently high depressive symptoms were associated with elevated adjusted hazard of all-cause stroke (adjusted hazards ratio, 1.65; 95\% confidence interval, 1.06-2.56). No evidence for effect modification by race, age, or sex was found.

CONCLUSIONS: Persistently high symptoms of depression predicted elevated hazard of stroke. Participants with improved depressive symptoms had no elevation in stroke risk. Such findings suggest that strategies to reduce depressive symptoms may ameliorate stroke risk.

}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.116.013554}, author = {Gilsanz, Paola and Kubzansky, Laura D and Tchetgen Tchetgen, Eric J and Wang, Qianyi and Kawachi, Ichiro and Patton, Kristen K and Fitzpatrick, Annette L and Kop, Willem J and Longstreth, W T and Glymour, M Maria} } @article {7260, title = {Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer{\textquoteright}s Disease.}, journal = {PLoS Genet}, volume = {12}, year = {2016}, month = {2016 Oct}, pages = {e1006327}, abstract = {

We performed an exome-wide association analysis in 1393 late-onset Alzheimer{\textquoteright}s disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5\% versus <0.05\% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95\% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.

}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006327}, author = {Jakobsdottir, Johanna and van der Lee, Sven J and Bis, Joshua C and Chouraki, Vincent and Li-Kroeger, David and Yamamoto, Shinya and Grove, Megan L and Naj, Adam and Vronskaya, Maria and Salazar, Jose L and DeStefano, Anita L and Brody, Jennifer A and Smith, Albert V and Amin, Najaf and Sims, Rebecca and Ibrahim-Verbaas, Carla A and Choi, Seung-Hoan and Satizabal, Claudia L and Lopez, Oscar L and Beiser, Alexa and Ikram, M Arfan and Garcia, Melissa E and Hayward, Caroline and Varga, Tibor V and Ripatti, Samuli and Franks, Paul W and Hallmans, G{\"o}ran and Rolandsson, Olov and Jansson, Jan-H{\r a}kon and Porteous, David J and Salomaa, Veikko and Eiriksdottir, Gudny and Rice, Kenneth M and Bellen, Hugo J and Levy, Daniel and Uitterlinden, Andr{\'e} G and Emilsson, Valur and Rotter, Jerome I and Aspelund, Thor and O{\textquoteright}Donnell, Christopher J and Fitzpatrick, Annette L and Launer, Lenore J and Hofman, Albert and Wang, Li-San and Williams, Julie and Schellenberg, Gerard D and Boerwinkle, Eric and Psaty, Bruce M and Seshadri, Sudha and Shulman, Joshua M and Gudnason, Vilmundur and van Duijn, Cornelia M} } @article {6932, title = {Study of Cardiovascular Health Outcomes in the Era of Claims Data: The Cardiovascular Health Study.}, journal = {Circulation}, volume = {133}, year = {2016}, month = {2016 Jan 12}, pages = {156-64}, abstract = {

BACKGROUND: Increasingly, the diagnostic codes from administrative claims data are being used as clinical outcomes.

METHODS AND RESULTS: Data from the Cardiovascular Health Study (CHS) were used to compare event rates and risk factor associations between adjudicated hospitalized cardiovascular events and claims-based methods of defining events. The outcomes of myocardial infarction (MI), stroke, and heart failure were defined in 3 ways: the CHS adjudicated event (CHS[adj]), selected International Classification of Diseases, Ninth Edition diagnostic codes only in the primary position for Medicare claims data from the Center for Medicare \& Medicaid Services (CMS[1st]), and the same selected diagnostic codes in any position (CMS[any]). Conventional claims-based methods of defining events had high positive predictive values but low sensitivities. For instance, the positive predictive value of International Classification of Diseases, Ninth Edition code 410.x1 for a new acute MI in the first position was 90.6\%, but this code identified only 53.8\% of incident MIs. The observed event rates for CMS[1st] were low. For MI, the incidence was 14.9 events per 1000 person-years for CHS[adj] MI, 8.6 for CMS[1st] MI, and 12.2 for CMS[any] MI. In general, cardiovascular disease risk factor associations were similar across the 3 methods of defining events. Indeed, traditional cardiovascular disease risk factors were also associated with all first hospitalizations not resulting from an MI.

CONCLUSIONS: The use of diagnostic codes from claims data as clinical events, especially when restricted to primary diagnoses, leads to an underestimation of event rates. Additionally, claims-based events data represent a composite end point that includes the outcome of interest and selected (misclassified) nonevent hospitalizations.

}, keywords = {Blood Glucose, Cardiovascular Diseases, Female, Follow-Up Studies, Health Surveys, Hospitalization, Hospitals, Veterans, Humans, Insurance Claim Review, International Classification of Diseases, Lipids, Male, Managed Care Programs, Medicare, Risk Factors, Sampling Studies, Treatment Outcome, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.115.018610}, author = {Psaty, Bruce M and Delaney, Joseph A and Arnold, Alice M and Curtis, Lesley H and Fitzpatrick, Annette L and Heckbert, Susan R and McKnight, Barbara and Ives, Diane and Gottdiener, John S and Kuller, Lewis H and Longstreth, W T} } @article {7563, title = {Concordance With Prevention Guidelines and Subsequent Cancer, Cardiovascular Disease, and Mortality: A Longitudinal Study of Older Adults.}, journal = {Am J Epidemiol}, volume = {186}, year = {2017}, month = {2017 Nov 15}, pages = {1168-1179}, abstract = {

Reports on the associations between multiple clinical and behavioral health indicators and major health outcomes among older adults are scarce. We prospectively examined concordance with guidelines from the American Cancer Society and American Heart Association for disease prevention in relation to cancer, cardiovascular disease (CVD), and mortality among Cardiovascular Health Study enrollees aged 65-98 years who, at baseline assessment in 1989-1996 (n = 3,491), were free of CVD and cancer. Total and cause-specific mortality, as well as incidence of cancer and CVD, were lower with higher guideline concordance. Independent of body mass index, blood pressure, total cholesterol, and fasting plasma glucose, better health behaviors (diet, physical activity, and alcohol consumption) were associated with lower mortality (2-sided P < 0.0001). Among individuals with ideal levels for 3-4 of these 4 cardiometabolic biomarkers, those with poor concordance with health behavior recommendations had higher mortality compared with those who had the highest concordance with these behavioral recommendations (adjusted mortality hazard ratio = 1.82, 95\% confidence interval: 1.25, 2.67). Older adults who are concordant with recommendations for cancer and CVD prevention have reduced rates of chronic disease and mortality. Interventions to achieve and maintain healthy lifestyle behaviors may offer benefits both in the presence and absence of adverse traditional clinical risk factors.

}, keywords = {Aged, Aged, 80 and over, American Cancer Society, American Heart Association, Body Mass Index, Cardiovascular Diseases, Cause of Death, Diet, Exercise, Female, Guideline Adherence, Healthy Lifestyle, Humans, Incidence, Longitudinal Studies, Male, Neoplasms, Practice Guidelines as Topic, Prospective Studies, United States}, issn = {1476-6256}, doi = {10.1093/aje/kwx150}, author = {Greenlee, Heather and Strizich, Garrett and Lovasi, Gina S and Kaplan, Robert C and Biggs, Mary L and Li, Christopher I and Richardson, John and Burke, Gregory L and Fitzpatrick, Annette L and Fretts, Amanda M and Psaty, Bruce M and Fried, Linda P} } @article {7587, title = {Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer{\textquoteright}s disease.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Sep}, pages = {1373-1384}, abstract = {

We identified rare coding variants associated with Alzheimer{\textquoteright}s disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 {\texttimes} 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 {\texttimes} 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer{\textquoteright}s disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 {\texttimes} 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 {\texttimes} 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 {\texttimes} 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer{\textquoteright}s disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer{\textquoteright}s disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer{\textquoteright}s disease.

}, keywords = {Adaptor Proteins, Signal Transducing, Alzheimer Disease, Amino Acid Sequence, Case-Control Studies, Exome, Gene Expression Profiling, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Immunity, Innate, Linkage Disequilibrium, Membrane Glycoproteins, Microglia, Odds Ratio, Phospholipase C gamma, Polymorphism, Single Nucleotide, Protein Interaction Maps, Receptors, Immunologic, Sequence Homology, Amino Acid}, issn = {1546-1718}, doi = {10.1038/ng.3916}, author = {Sims, Rebecca and van der Lee, Sven J and Naj, Adam C and Bellenguez, C{\'e}line and Badarinarayan, Nandini and Jakobsdottir, Johanna and Kunkle, Brian W and Boland, Anne and Raybould, Rachel and Bis, Joshua C and Martin, Eden R and Grenier-Boley, Benjamin and Heilmann-Heimbach, Stefanie and Chouraki, Vincent and Kuzma, Amanda B and Sleegers, Kristel and Vronskaya, Maria and Ruiz, Agustin and Graham, Robert R and Olaso, Robert and Hoffmann, Per and Grove, Megan L and Vardarajan, Badri N and Hiltunen, Mikko and N{\"o}then, Markus M and White, Charles C and Hamilton-Nelson, Kara L and Epelbaum, Jacques and Maier, Wolfgang and Choi, Seung-Hoan and Beecham, Gary W and Dulary, C{\'e}cile and Herms, Stefan and Smith, Albert V and Funk, Cory C and Derbois, C{\'e}line and Forstner, Andreas J and Ahmad, Shahzad and Li, Hongdong and Bacq, Delphine and Harold, Denise and Satizabal, Claudia L and Valladares, Otto and Squassina, Alessio and Thomas, Rhodri and Brody, Jennifer A and Qu, Liming and S{\'a}nchez-Juan, Pascual and Morgan, Taniesha and Wolters, Frank J and Zhao, Yi and Garcia, Florentino Sanchez and Denning, Nicola and Fornage, Myriam and Malamon, John and Naranjo, Maria Candida Deniz and Majounie, Elisa and Mosley, Thomas H and Dombroski, Beth and Wallon, David and Lupton, Michelle K and Dupuis, Jos{\'e}e and Whitehead, Patrice and Fratiglioni, Laura and Medway, Christopher and Jian, Xueqiu and Mukherjee, Shubhabrata and Keller, Lina and Brown, Kristelle and Lin, Honghuang and Cantwell, Laura B and Panza, Francesco and McGuinness, Bernadette and Moreno-Grau, Sonia and Burgess, Jeremy D and Solfrizzi, Vincenzo and Proitsi, Petra and Adams, Hieab H and Allen, Mariet and Seripa, Davide and Pastor, Pau and Cupples, L Adrienne and Price, Nathan D and Hannequin, Didier and Frank-Garc{\'\i}a, Ana and Levy, Daniel and Chakrabarty, Paramita and Caffarra, Paolo and Giegling, Ina and Beiser, Alexa S and Giedraitis, Vilmantas and Hampel, Harald and Garcia, Melissa E and Wang, Xue and Lannfelt, Lars and Mecocci, Patrizia and Eiriksdottir, Gudny and Crane, Paul K and Pasquier, Florence and Boccardi, Virginia and Hen{\'a}ndez, Isabel and Barber, Robert C and Scherer, Martin and Tarraga, Lluis and Adams, Perrie M and Leber, Markus and Chen, Yuning and Albert, Marilyn S and Riedel-Heller, Steffi and Emilsson, Valur and Beekly, Duane and Braae, Anne and Schmidt, Reinhold and Blacker, Deborah and Masullo, Carlo and Schmidt, Helena and Doody, Rachelle S and Spalletta, Gianfranco and Jr, W T Longstreth and Fairchild, Thomas J and Boss{\`u}, Paola and Lopez, Oscar L and Frosch, Matthew P and Sacchinelli, Eleonora and Ghetti, Bernardino and Yang, Qiong and Huebinger, Ryan M and Jessen, Frank and Li, Shuo and Kamboh, M Ilyas and Morris, John and Sotolongo-Grau, Oscar and Katz, Mindy J and Corcoran, Chris and Dunstan, Melanie and Braddel, Amy and Thomas, Charlene and Meggy, Alun and Marshall, Rachel and Gerrish, Amy and Chapman, Jade and Aguilar, Miquel and Taylor, Sarah and Hill, Matt and Fair{\'e}n, M{\`o}nica D{\'\i}ez and Hodges, Angela and Vellas, Bruno and Soininen, Hilkka and Kloszewska, Iwona and Daniilidou, Makrina and Uphill, James and Patel, Yogen and Hughes, Joseph T and Lord, Jenny and Turton, James and Hartmann, Annette M and Cecchetti, Roberta and Fenoglio, Chiara and Serpente, Maria and Arcaro, Marina and Caltagirone, Carlo and Orfei, Maria Donata and Ciaramella, Antonio and Pichler, Sabrina and Mayhaus, Manuel and Gu, Wei and Lleo, Alberto and Fortea, Juan and Blesa, Rafael and Barber, Imelda S and Brookes, Keeley and Cupidi, Chiara and Maletta, Raffaele Giovanni and Carrell, David and Sorbi, Sandro and Moebus, Susanne and Urbano, Maria and Pilotto, Alberto and Kornhuber, Johannes and Bosco, Paolo and Todd, Stephen and Craig, David and Johnston, Janet and Gill, Michael and Lawlor, Brian and Lynch, Aoibhinn and Fox, Nick C and Hardy, John and Albin, Roger L and Apostolova, Liana G and Arnold, Steven E and Asthana, Sanjay and Atwood, Craig S and Baldwin, Clinton T and Barnes, Lisa L and Barral, Sandra and Beach, Thomas G and Becker, James T and Bigio, Eileen H and Bird, Thomas D and Boeve, Bradley F and Bowen, James D and Boxer, Adam and Burke, James R and Burns, Jeffrey M and Buxbaum, Joseph D and Cairns, Nigel J and Cao, Chuanhai and Carlson, Chris S and Carlsson, Cynthia M and Carney, Regina M and Carrasquillo, Minerva M and Carroll, Steven L and Diaz, Carolina Ceballos and Chui, Helena C and Clark, David G and Cribbs, David H and Crocco, Elizabeth A and DeCarli, Charles and Dick, Malcolm and Duara, Ranjan and Evans, Denis A and Faber, Kelley M and Fallon, Kenneth B and Fardo, David W and Farlow, Martin R and Ferris, Steven and Foroud, Tatiana M and Galasko, Douglas R and Gearing, Marla and Geschwind, Daniel H and Gilbert, John R and Graff-Radford, Neill R and Green, Robert C and Growdon, John H and Hamilton, Ronald L and Harrell, Lindy E and Honig, Lawrence S and Huentelman, Matthew J and Hulette, Christine M and Hyman, Bradley T and Jarvik, Gail P and Abner, Erin and Jin, Lee-Way and Jun, Gyungah and Karydas, Anna and Kaye, Jeffrey A and Kim, Ronald and Kowall, Neil W and Kramer, Joel H and LaFerla, Frank M and Lah, James J and Leverenz, James B and Levey, Allan I and Li, Ge and Lieberman, Andrew P and Lunetta, Kathryn L and Lyketsos, Constantine G and Marson, Daniel C and Martiniuk, Frank and Mash, Deborah C and Masliah, Eliezer and McCormick, Wayne C and McCurry, Susan M and McDavid, Andrew N and McKee, Ann C and Mesulam, Marsel and Miller, Bruce L and Miller, Carol A and Miller, Joshua W and Morris, John C and Murrell, Jill R and Myers, Amanda J and O{\textquoteright}Bryant, Sid and Olichney, John M and Pankratz, Vernon S and Parisi, Joseph E and Paulson, Henry L and Perry, William and Peskind, Elaine and Pierce, Aimee and Poon, Wayne W and Potter, Huntington and Quinn, Joseph F and Raj, Ashok and Raskind, Murray and Reisberg, Barry and Reitz, Christiane and Ringman, John M and Roberson, Erik D and Rogaeva, Ekaterina and Rosen, Howard J and Rosenberg, Roger N and Sager, Mark A and Saykin, Andrew J and Schneider, Julie A and Schneider, Lon S and Seeley, William W and Smith, Amanda G and Sonnen, Joshua A and Spina, Salvatore and Stern, Robert A and Swerdlow, Russell H and Tanzi, Rudolph E and Thornton-Wells, Tricia A and Trojanowski, John Q and Troncoso, Juan C and Van Deerlin, Vivianna M and Van Eldik, Linda J and Vinters, Harry V and Vonsattel, Jean Paul and Weintraub, Sandra and Welsh-Bohmer, Kathleen A and Wilhelmsen, Kirk C and Williamson, Jennifer and Wingo, Thomas S and Woltjer, Randall L and Wright, Clinton B and Yu, Chang-En and Yu, Lei and Garzia, Fabienne and Golamaully, Feroze and Septier, Gislain and Engelborghs, Sebastien and Vandenberghe, Rik and De Deyn, Peter P and Fernadez, Carmen Mu{\~n}oz and Benito, Yoland Aladro and Thonberg, H{\r a}kan and Forsell, Charlotte and Lilius, Lena and Kinhult-St{\r a}hlbom, Anne and Kilander, Lena and Brundin, RoseMarie and Concari, Letizia and Helisalmi, Seppo and Koivisto, Anne Maria and Haapasalo, Annakaisa and Dermecourt, Vincent and Fi{\'e}vet, Nathalie and Hanon, Olivier and Dufouil, Carole and Brice, Alexis and Ritchie, Karen and Dubois, Bruno and Himali, Jayanadra J and Keene, C Dirk and Tschanz, JoAnn and Fitzpatrick, Annette L and Kukull, Walter A and Norton, Maria and Aspelund, Thor and Larson, Eric B and Munger, Ron and Rotter, Jerome I and Lipton, Richard B and Bullido, Mar{\'\i}a J and Hofman, Albert and Montine, Thomas J and Coto, Eliecer and Boerwinkle, Eric and Petersen, Ronald C and Alvarez, Victoria and Rivadeneira, Fernando and Reiman, Eric M and Gallo, Maura and O{\textquoteright}Donnell, Christopher J and Reisch, Joan S and Bruni, Amalia Cecilia and Royall, Donald R and Dichgans, Martin and Sano, Mary and Galimberti, Daniela and St George-Hyslop, Peter and Scarpini, Elio and Tsuang, Debby W and Mancuso, Michelangelo and Bonuccelli, Ubaldo and Winslow, Ashley R and Daniele, Antonio and Wu, Chuang-Kuo and Peters, Oliver and Nacmias, Benedetta and Riemenschneider, Matthias and Heun, Reinhard and Brayne, Carol and Rubinsztein, David C and Bras, Jose and Guerreiro, Rita and Al-Chalabi, Ammar and Shaw, Christopher E and Collinge, John and Mann, David and Tsolaki, Magda and Clarimon, Jordi and Sussams, Rebecca and Lovestone, Simon and O{\textquoteright}Donovan, Michael C and Owen, Michael J and Behrens, Timothy W and Mead, Simon and Goate, Alison M and Uitterlinden, Andr{\'e} G and Holmes, Clive and Cruchaga, Carlos and Ingelsson, Martin and Bennett, David A and Powell, John and Golde, Todd E and Graff, Caroline and De Jager, Philip L and Morgan, Kevin and Ertekin-Taner, Nilufer and Combarros, Onofre and Psaty, Bruce M and Passmore, Peter and Younkin, Steven G and Berr, Claudine and Gudnason, Vilmundur and Rujescu, Dan and Dickson, Dennis W and Dartigues, Jean-Fran{\c c}ois and DeStefano, Anita L and Ortega-Cubero, Sara and Hakonarson, Hakon and Campion, Dominique and Boada, Merce and Kauwe, John Keoni and Farrer, Lindsay A and Van Broeckhoven, Christine and Ikram, M Arfan and Jones, Lesley and Haines, Jonathan L and Tzourio, Christophe and Launer, Lenore J and Escott-Price, Valentina and Mayeux, Richard and Deleuze, Jean-Francois and Amin, Najaf and Holmans, Peter A and Pericak-Vance, Margaret A and Amouyel, Philippe and van Duijn, Cornelia M and Ramirez, Alfredo and Wang, Li-San and Lambert, Jean-Charles and Seshadri, Sudha and Williams, Julie and Schellenberg, Gerard D} } @article {7591, title = {Telomeres and the natural lifespan limit in humans.}, journal = {Aging (Albany NY)}, volume = {9}, year = {2017}, month = {2017 Apr}, pages = {1130-1142}, abstract = {

An ongoing debate in demography has focused on whether the human lifespan has a maximal natural limit. Taking a mechanistic perspective, and knowing that short telomeres are associated with diminished longevity, we examined whether telomere length dynamics during adult life could set a maximal natural lifespan limit. We define leukocyte telomere length of 5 kb as the {\textquoteright}telomeric brink{\textquoteright}, which denotes a high risk of imminent death. We show that a subset of adults may reach the telomeric brink within the current life expectancy and more so for a 100-year life expectancy. Thus, secular trends in life expectancy should confront a biological limit due to crossing the telomeric brink.

}, issn = {1945-4589}, doi = {10.18632/aging.101216}, author = {Steenstrup, Troels and Kark, Jeremy D and Verhulst, Simon and Thinggaard, Mikael and Hjelmborg, Jacob V B and Dalg{\r a}rd, Christine and Kyvik, Kirsten Ohm and Christiansen, Lene and Mangino, Massimo and Spector, Timothy D and Petersen, Inge and Kimura, Masayuki and Benetos, Athanase and Labat, Carlos and Sinnreich, Ronit and Hwang, Shih-Jen and Levy, Daniel and Hunt, Steven C and Fitzpatrick, Annette L and Chen, Wei and Berenson, Gerald S and Barbieri, Michelangela and Paolisso, Giuseppe and Gadalla, Shahinaz M and Savage, Sharon A and Christensen, Kaare and Yashin, Anatoliy I and Arbeev, Konstantin G and Aviv, Abraham} } @article {8043, title = {Demographic-Specific Rates for Life Events in the Cardiovascular Health Study and Comparisons With Other Studies.}, journal = {Innov Aging}, volume = {2}, year = {2018}, month = {2018 Jan}, pages = {igy005}, abstract = {

Purpose of the Study: (1a) We use the Cardiovascular Health Study (CHS), a multi-site heterogeneous sample of Medicare enrollees ( = 5,849) to provide rates for specific life events experienced within 6 months; (1b) We present rates for 29 other studies of community-residing older adults ( = 41,308); (2) For the CHS, we provide demographic-specific rates and predicted probabilities for age [young-old (65-75) vs old-old (>=75)], gender, race, marital status, and education.

Design/Methods: The CHS sample is 57.6\% women, 84.2\% white (15.8\% black), and 66.3\% married. Mean age is 72.8 years (standard deviation [] = 5.6, range = 65-100) and education is 13.7 years ( = 4.8). Life events were interviewer-assessed. Regressions estimated associations of life event rates with demographic groups (e.g., age), controlling for other demographic variables (e.g., gender, etc.).

Results: (1a) CHS rates ranged from 44.7\% (death of someone close) to 1.1\% (retirement/work changes). (1b) Most life event studies used total scores and only 5 that met our inclusion criteria used time intervals <1 year; longer intervals were associated with higher rates. (2) In the CHS, the life event for illnesses was related to 5 demographic variables (net the other 4 demographic variables), difficulties caregiving to 4, and worse relationships to 3 demographic variables. Race was related to 8 life events, marital status to 7, education to 6, and age to 4 events.

Implications: By identifying demographic groups at highest risk for life events, this research focuses on older adults at greatest risk for health problems. These data are necessary for translating research into interventions, practice, and policy.

}, issn = {2399-5300}, doi = {10.1093/geroni/igy005}, author = {Vitaliano, Peter P and Fitzpatrick, Annette L and Williams, Lee E and Montano, Michalina A and Russo, Joan E} } @article {8539, title = {Metabolic Clusters and Outcomes in Older Adults: The Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {66}, year = {2018}, month = {2018 02}, pages = {289-296}, abstract = {

BACKGROUND/OBJECTIVES: Few studies have the requisite phenotypic information to define metabolic patterns that may inform our understanding of the pathophysiology and consequences of diabetes in older adults. We sought to characterize clusters of older adults on the basis of shared metabolic features.

DESIGN: Population-based prospective cohort study.

SETTING: Four U.S. Cardiovascular Health Study field centers.

PARTICIPANTS: Individuals aged 65 and older taking no glucose-lowering agents (N~=~2,231).

MEASUREMENTS: K-means cluster analysis of 11 metabolic parameters (fasting and postload serum glucose and plasma insulin, fasting C-peptide, body mass index, C-reactive protein (CRP), estimated glomerular filtration rate (eGFR), albuminuria, carboxymethyl lysine (an advanced glycation end-product), procollagen III N-terminal propeptide (a fibrotic marker)) and their associations with incident cardiovascular disease, diabetes, disability, and mortality over 8 to 14.5~years of follow-up and with measures of subclinical cardiovascular disease.

RESULTS: A 6-cluster solution provided robust differentiation into distinct, identifiable clusters. Cluster A (n~=~739) had the lowest glucose and insulin and highest eGFR and the lowest rates of all outcomes. Cluster B (n~=~419) had high glucose and insulin and intermediate rates of most outcomes. Cluster C (n~=~118) had the highest insulin. Cluster D (n~=~129) had the highest glucose with much lower insulin. Cluster E (n~=~314) had the lowest eGFR and highest albuminuria. Cluster F (n~=~512) had the highest CRP. Rates of CVD, mortality, and subclinical atherosclerosis were highest in clusters C, D, and E and were similar to rates in participants with treated diabetes. Incidence of disability was highest in Cluster C.

CONCLUSION: Clustering according to metabolic parameters identifies distinct phenotypes that are strongly associated with clinical and functional outcomes, even at advanced age.

}, keywords = {Aged, Aged, 80 and over, Blood Glucose, C-Reactive Protein, Cardiovascular Diseases, Diabetes Mellitus, Female, Glomerular Filtration Rate, Humans, Incidence, Insulin, Longitudinal Studies, Male, Prospective Studies, Risk Factors, United States}, issn = {1532-5415}, doi = {10.1111/jgs.15205}, author = {Mukamal, Kenneth J and Siscovick, David S and de Boer, Ian H and Ix, Joachim H and Kizer, Jorge R and Djouss{\'e}, Luc and Fitzpatrick, Annette L and Tracy, Russell P and Boyko, Edward J and Kahn, Steven E and Arnold, Alice M} } @article {7788, title = {Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 May 29}, pages = {2098}, abstract = {

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 {\texttimes} 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3\% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-04362-x}, author = {Davies, Gail and Lam, Max and Harris, Sarah E and Trampush, Joey W and Luciano, Michelle and Hill, W David and Hagenaars, Saskia P and Ritchie, Stuart J and Marioni, Riccardo E and Fawns-Ritchie, Chloe and Liewald, David C M and Okely, Judith A and Ahola-Olli, Ari V and Barnes, Catriona L K and Bertram, Lars and Bis, Joshua C and Burdick, Katherine E and Christoforou, Andrea and DeRosse, Pamela and Djurovic, Srdjan and Espeseth, Thomas and Giakoumaki, Stella and Giddaluru, Sudheer and Gustavson, Daniel E and Hayward, Caroline and Hofer, Edith and Ikram, M Arfan and Karlsson, Robert and Knowles, Emma and Lahti, Jari and Leber, Markus and Li, Shuo and Mather, Karen A and Melle, Ingrid and Morris, Derek and Oldmeadow, Christopher and Palviainen, Teemu and Payton, Antony and Pazoki, Raha and Petrovic, Katja and Reynolds, Chandra A and Sargurupremraj, Muralidharan and Scholz, Markus and Smith, Jennifer A and Smith, Albert V and Terzikhan, Natalie and Thalamuthu, Anbupalam and Trompet, Stella and van der Lee, Sven J and Ware, Erin B and Windham, B Gwen and Wright, Margaret J and Yang, Jingyun and Yu, Jin and Ames, David and Amin, Najaf and Amouyel, Philippe and Andreassen, Ole A and Armstrong, Nicola J and Assareh, Amelia A and Attia, John R and Attix, Deborah and Avramopoulos, Dimitrios and Bennett, David A and B{\"o}hmer, Anne C and Boyle, Patricia A and Brodaty, Henry and Campbell, Harry and Cannon, Tyrone D and Cirulli, Elizabeth T and Congdon, Eliza and Conley, Emily Drabant and Corley, Janie and Cox, Simon R and Dale, Anders M and Dehghan, Abbas and Dick, Danielle and Dickinson, Dwight and Eriksson, Johan G and Evangelou, Evangelos and Faul, Jessica D and Ford, Ian and Freimer, Nelson A and Gao, He and Giegling, Ina and Gillespie, Nathan A and Gordon, Scott D and Gottesman, Rebecca F and Griswold, Michael E and Gudnason, Vilmundur and Harris, Tamara B and Hartmann, Annette M and Hatzimanolis, Alex and Heiss, Gerardo and Holliday, Elizabeth G and Joshi, Peter K and K{\"a}h{\"o}nen, Mika and Kardia, Sharon L R and Karlsson, Ida and Kleineidam, Luca and Knopman, David S and Kochan, Nicole A and Konte, Bettina and Kwok, John B and Le Hellard, Stephanie and Lee, Teresa and Lehtim{\"a}ki, Terho and Li, Shu-Chen and Liu, Tian and Koini, Marisa and London, Edythe and Longstreth, Will T and Lopez, Oscar L and Loukola, Anu and Luck, Tobias and Lundervold, Astri J and Lundquist, Anders and Lyytik{\"a}inen, Leo-Pekka and Martin, Nicholas G and Montgomery, Grant W and Murray, Alison D and Need, Anna C and Noordam, Raymond and Nyberg, Lars and Ollier, William and Papenberg, Goran and Pattie, Alison and Polasek, Ozren and Poldrack, Russell A and Psaty, Bruce M and Reppermund, Simone and Riedel-Heller, Steffi G and Rose, Richard J and Rotter, Jerome I and Roussos, Panos and Rovio, Suvi P and Saba, Yasaman and Sabb, Fred W and Sachdev, Perminder S and Satizabal, Claudia L and Schmid, Matthias and Scott, Rodney J and Scult, Matthew A and Simino, Jeannette and Slagboom, P Eline and Smyrnis, Nikolaos and Soumar{\'e}, A{\"\i}cha and Stefanis, Nikos C and Stott, David J and Straub, Richard E and Sundet, Kjetil and Taylor, Adele M and Taylor, Kent D and Tzoulaki, Ioanna and Tzourio, Christophe and Uitterlinden, Andre and Vitart, Veronique and Voineskos, Aristotle N and Kaprio, Jaakko and Wagner, Michael and Wagner, Holger and Weinhold, Leonie and Wen, K Hoyan and Widen, Elisabeth and Yang, Qiong and Zhao, Wei and Adams, Hieab H H and Arking, Dan E and Bilder, Robert M and Bitsios, Panos and Boerwinkle, Eric and Chiba-Falek, Ornit and Corvin, Aiden and De Jager, Philip L and Debette, Stephanie and Donohoe, Gary and Elliott, Paul and Fitzpatrick, Annette L and Gill, Michael and Glahn, David C and H{\"a}gg, Sara and Hansell, Narelle K and Hariri, Ahmad R and Ikram, M Kamran and Jukema, J Wouter and Vuoksimaa, Eero and Keller, Matthew C and Kremen, William S and Launer, Lenore and Lindenberger, Ulman and Palotie, Aarno and Pedersen, Nancy L and Pendleton, Neil and Porteous, David J and R{\"a}ikk{\"o}nen, Katri and Raitakari, Olli T and Ramirez, Alfredo and Reinvang, Ivar and Rudan, Igor and Schmidt, Reinhold and Schmidt, Helena and Schofield, Peter W and Schofield, Peter R and Starr, John M and Steen, Vidar M and Trollor, Julian N and Turner, Steven T and van Duijn, Cornelia M and Villringer, Arno and Weinberger, Daniel R and Weir, David R and Wilson, James F and Malhotra, Anil and McIntosh, Andrew M and Gale, Catharine R and Seshadri, Sudha and Mosley, Thomas H and Bressler, Jan and Lencz, Todd and Deary, Ian J} } @article {7971, title = {Alcohol consumption and leukocyte telomere length.}, journal = {Sci Rep}, volume = {9}, year = {2019}, month = {2019 Feb 05}, pages = {1404}, abstract = {

The relationship between alcohol consumption and mortality generally exhibits a U-shaped curve. The longevity observed with moderate alcohol consumption may be explained by other confounding factors, and, if such a relationship is present, the mechanism is not well understood. Indeed, the optimal amount of alcohol consumption for health has yet to be determined. Leukocyte telomere length is an emerging quantifiable marker of biological age and health, and a shorter telomere length is a predictor of increased mortality. Because leukocyte telomere length is a quantifiable and objectively measurable biomarker of aging, we sought to identify the amount of alcohol consumption associated with the longest telomere length and least telomere length attrition. Among over 2,000 participants from two distinct cohort studies, we found no pattern of alcohol consumption that was associated with longer telomere length or less telomere length attrition over time. Binge drinking may reduce telomere length. Using telomere length as a marker of age and health, these data fail to demonstrate any benefits of alcohol consumption, even when consumed in moderation.

}, issn = {2045-2322}, doi = {10.1038/s41598-019-38904-0}, author = {Dixit, Shalini and Whooley, Mary A and Vittinghoff, Eric and Roberts, Jason D and Heckbert, Susan R and Fitzpatrick, Annette L and Lin, Jue and Leung, Cindy and Mukamal, Kenneth J and Marcus, Gregory M} } @article {7977, title = {Genetic meta-analysis of diagnosed Alzheimer{\textquoteright}s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Mar}, pages = {414-430}, abstract = {

Risk for late-onset Alzheimer{\textquoteright}s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer{\textquoteright}s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer{\textquoteright}s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 {\texttimes} 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

}, issn = {1546-1718}, doi = {10.1038/s41588-019-0358-2}, author = {Kunkle, Brian W and Grenier-Boley, Benjamin and Sims, Rebecca and Bis, Joshua C and Damotte, Vincent and Naj, Adam C and Boland, Anne and Vronskaya, Maria and van der Lee, Sven J and Amlie-Wolf, Alexandre and Bellenguez, C{\'e}line and Frizatti, Aura and Chouraki, Vincent and Martin, Eden R and Sleegers, Kristel and Badarinarayan, Nandini and Jakobsdottir, Johanna and Hamilton-Nelson, Kara L and Moreno-Grau, Sonia and Olaso, Robert and Raybould, Rachel and Chen, Yuning and Kuzma, Amanda B and Hiltunen, Mikko and Morgan, Taniesha and Ahmad, Shahzad and Vardarajan, Badri N and Epelbaum, Jacques and Hoffmann, Per and Boada, Merce and Beecham, Gary W and Garnier, Jean-Guillaume and Harold, Denise and Fitzpatrick, Annette L and Valladares, Otto and Moutet, Marie-Laure and Gerrish, Amy and Smith, Albert V and Qu, Liming and Bacq, Delphine and Denning, Nicola and Jian, Xueqiu and Zhao, Yi and Del Zompo, Maria and Fox, Nick C and Choi, Seung-Hoan and Mateo, Ignacio and Hughes, Joseph T and Adams, Hieab H and Malamon, John and Sanchez-Garcia, Florentino and Patel, Yogen and Brody, Jennifer A and Dombroski, Beth A and Naranjo, Maria Candida Deniz and Daniilidou, Makrina and Eiriksdottir, Gudny and Mukherjee, Shubhabrata and Wallon, David and Uphill, James and Aspelund, Thor and Cantwell, Laura B and Garzia, Fabienne and Galimberti, Daniela and Hofer, Edith and Butkiewicz, Mariusz and Fin, Bertrand and Scarpini, Elio and Sarnowski, Chloe and Bush, Will S and Meslage, St{\'e}phane and Kornhuber, Johannes and White, Charles C and Song, Yuenjoo and Barber, Robert C and Engelborghs, Sebastiaan and Sordon, Sabrina and Voijnovic, Dina and Adams, Perrie M and Vandenberghe, Rik and Mayhaus, Manuel and Cupples, L Adrienne and Albert, Marilyn S and De Deyn, Peter P and Gu, Wei and Himali, Jayanadra J and Beekly, Duane and Squassina, Alessio and Hartmann, Annette M and Orellana, Adelina and Blacker, Deborah and Rodriguez-Rodriguez, Eloy and Lovestone, Simon and Garcia, Melissa E and Doody, Rachelle S and Munoz-Fernadez, Carmen and Sussams, Rebecca and Lin, Honghuang and Fairchild, Thomas J and Benito, Yolanda A and Holmes, Clive and Karamuji{\'c}-{\v C}omi{\'c}, Hata and Frosch, Matthew P and Thonberg, H{\r a}kan and Maier, Wolfgang and Roschupkin, Gena and Ghetti, Bernardino and Giedraitis, Vilmantas and Kawalia, Amit and Li, Shuo and Huebinger, Ryan M and Kilander, Lena and Moebus, Susanne and Hernandez, Isabel and Kamboh, M Ilyas and Brundin, RoseMarie and Turton, James and Yang, Qiong and Katz, Mindy J and Concari, Letizia and Lord, Jenny and Beiser, Alexa S and Keene, C Dirk and Helisalmi, Seppo and Kloszewska, Iwona and Kukull, Walter A and Koivisto, Anne Maria and Lynch, Aoibhinn and Tarraga, Lluis and Larson, Eric B and Haapasalo, Annakaisa and Lawlor, Brian and Mosley, Thomas H and Lipton, Richard B and Solfrizzi, Vincenzo and Gill, Michael and Longstreth, W T and Montine, Thomas J and Frisardi, Vincenza and Diez-Fairen, Monica and Rivadeneira, Fernando and Petersen, Ronald C and Deramecourt, Vincent and Alvarez, Ignacio and Salani, Francesca and Ciaramella, Antonio and Boerwinkle, Eric and Reiman, Eric M and Fi{\'e}vet, Nathalie and Rotter, Jerome I and Reisch, Joan S and Hanon, Olivier and Cupidi, Chiara and Andre Uitterlinden, A G and Royall, Donald R and Dufouil, Carole and Maletta, Raffaele Giovanni and de Rojas, Itziar and Sano, Mary and Brice, Alexis and Cecchetti, Roberta and George-Hyslop, Peter St and Ritchie, Karen and Tsolaki, Magda and Tsuang, Debby W and Dubois, Bruno and Craig, David and Wu, Chuang-Kuo and Soininen, Hilkka and Avramidou, Despoina and Albin, Roger L and Fratiglioni, Laura and Germanou, Antonia and Apostolova, Liana G and Keller, Lina and Koutroumani, Maria and Arnold, Steven E and Panza, Francesco and Gkatzima, Olymbia and Asthana, Sanjay and Hannequin, Didier and Whitehead, Patrice and Atwood, Craig S and Caffarra, Paolo and Hampel, Harald and Quintela, In{\'e}s and Carracedo, Angel and Lannfelt, Lars and Rubinsztein, David C and Barnes, Lisa L and Pasquier, Florence and Fr{\"o}lich, Lutz and Barral, Sandra and McGuinness, Bernadette and Beach, Thomas G and Johnston, Janet A and Becker, James T and Passmore, Peter and Bigio, Eileen H and Schott, Jonathan M and Bird, Thomas D and Warren, Jason D and Boeve, Bradley F and Lupton, Michelle K and Bowen, James D and Proitsi, Petra and Boxer, Adam and Powell, John F and Burke, James R and Kauwe, John S K and Burns, Jeffrey M and Mancuso, Michelangelo and Buxbaum, Joseph D and Bonuccelli, Ubaldo and Cairns, Nigel J and McQuillin, Andrew and Cao, Chuanhai and Livingston, Gill and Carlson, Chris S and Bass, Nicholas J and Carlsson, Cynthia M and Hardy, John and Carney, Regina M and Bras, Jose and Carrasquillo, Minerva M and Guerreiro, Rita and Allen, Mariet and Chui, Helena C and Fisher, Elizabeth and Masullo, Carlo and Crocco, Elizabeth A and DeCarli, Charles and Bisceglio, Gina and Dick, Malcolm and Ma, Li and Duara, Ranjan and Graff-Radford, Neill R and Evans, Denis A and Hodges, Angela and Faber, Kelley M and Scherer, Martin and Fallon, Kenneth B and Riemenschneider, Matthias and Fardo, David W and Heun, Reinhard and Farlow, Martin R and K{\"o}lsch, Heike and Ferris, Steven and Leber, Markus and Foroud, Tatiana M and Heuser, Isabella and Galasko, Douglas R and Giegling, Ina and Gearing, Marla and H{\"u}ll, Michael and Geschwind, Daniel H and Gilbert, John R and Morris, John and Green, Robert C and Mayo, Kevin and Growdon, John H and Feulner, Thomas and Hamilton, Ronald L and Harrell, Lindy E and Drichel, Dmitriy and Honig, Lawrence S and Cushion, Thomas D and Huentelman, Matthew J and Hollingworth, Paul and Hulette, Christine M and Hyman, Bradley T and Marshall, Rachel and Jarvik, Gail P and Meggy, Alun and Abner, Erin and Menzies, Georgina E and Jin, Lee-Way and Leonenko, Ganna and Real, Luis M and Jun, Gyungah R and Baldwin, Clinton T and Grozeva, Detelina and Karydas, Anna and Russo, Giancarlo and Kaye, Jeffrey A and Kim, Ronald and Jessen, Frank and Kowall, Neil W and Vellas, Bruno and Kramer, Joel H and Vardy, Emma and LaFerla, Frank M and J{\"o}ckel, Karl-Heinz and Lah, James J and Dichgans, Martin and Leverenz, James B and Mann, David and Levey, Allan I and Pickering-Brown, Stuart and Lieberman, Andrew P and Klopp, Norman and Lunetta, Kathryn L and Wichmann, H-Erich and Lyketsos, Constantine G and Morgan, Kevin and Marson, Daniel C and Brown, Kristelle and Martiniuk, Frank and Medway, Christopher and Mash, Deborah C and N{\"o}then, Markus M and Masliah, Eliezer and Hooper, Nigel M and McCormick, Wayne C and Daniele, Antonio and McCurry, Susan M and Bayer, Anthony and McDavid, Andrew N and Gallacher, John and McKee, Ann C and van den Bussche, Hendrik and Mesulam, Marsel and Brayne, Carol and Miller, Bruce L and Riedel-Heller, Steffi and Miller, Carol A and Miller, Joshua W and Al-Chalabi, Ammar and Morris, John C and Shaw, Christopher E and Myers, Amanda J and Wiltfang, Jens and O{\textquoteright}Bryant, Sid and Olichney, John M and Alvarez, Victoria and Parisi, Joseph E and Singleton, Andrew B and Paulson, Henry L and Collinge, John and Perry, William R and Mead, Simon and Peskind, Elaine and Cribbs, David H and Rossor, Martin and Pierce, Aimee and Ryan, Natalie S and Poon, Wayne W and Nacmias, Benedetta and Potter, Huntington and Sorbi, Sandro and Quinn, Joseph F and Sacchinelli, Eleonora and Raj, Ashok and Spalletta, Gianfranco and Raskind, Murray and Caltagirone, Carlo and Boss{\`u}, Paola and Orfei, Maria Donata and Reisberg, Barry and Clarke, Robert and Reitz, Christiane and Smith, A David and Ringman, John M and Warden, Donald and Roberson, Erik D and Wilcock, Gordon and Rogaeva, Ekaterina and Bruni, Amalia Cecilia and Rosen, Howard J and Gallo, Maura and Rosenberg, Roger N and Ben-Shlomo, Yoav and Sager, Mark A and Mecocci, Patrizia and Saykin, Andrew J and Pastor, Pau and Cuccaro, Michael L and Vance, Jeffery M and Schneider, Julie A and Schneider, Lori S and Slifer, Susan and Seeley, William W and Smith, Amanda G and Sonnen, Joshua A and Spina, Salvatore and Stern, Robert A and Swerdlow, Russell H and Tang, Mitchell and Tanzi, Rudolph E and Trojanowski, John Q and Troncoso, Juan C and Van Deerlin, Vivianna M and Van Eldik, Linda J and Vinters, Harry V and Vonsattel, Jean Paul and Weintraub, Sandra and Welsh-Bohmer, Kathleen A and Wilhelmsen, Kirk C and Williamson, Jennifer and Wingo, Thomas S and Woltjer, Randall L and Wright, Clinton B and Yu, Chang-En and Yu, Lei and Saba, Yasaman and Pilotto, Alberto and Bullido, Mar{\'\i}a J and Peters, Oliver and Crane, Paul K and Bennett, David and Bosco, Paola and Coto, Eliecer and Boccardi, Virginia and De Jager, Phil L and Lleo, Alberto and Warner, Nick and Lopez, Oscar L and Ingelsson, Martin and Deloukas, Panagiotis and Cruchaga, Carlos and Graff, Caroline and Gwilliam, Rhian and Fornage, Myriam and Goate, Alison M and S{\'a}nchez-Juan, Pascual and Kehoe, Patrick G and Amin, Najaf and Ertekin-Taner, Nilifur and Berr, Claudine and Debette, Stephanie and Love, Seth and Launer, Lenore J and Younkin, Steven G and Dartigues, Jean-Fran{\c c}ois and Corcoran, Chris and Ikram, M Arfan and Dickson, Dennis W and Nicolas, Ga{\"e}l and Campion, Dominique and Tschanz, JoAnn and Schmidt, Helena and Hakonarson, Hakon and Clarimon, Jordi and Munger, Ron and Schmidt, Reinhold and Farrer, Lindsay A and Van Broeckhoven, Christine and C O{\textquoteright}Donovan, Michael and DeStefano, Anita L and Jones, Lesley and Haines, Jonathan L and Deleuze, Jean-Francois and Owen, Michael J and Gudnason, Vilmundur and Mayeux, Richard and Escott-Price, Valentina and Psaty, Bruce M and Ramirez, Alfredo and Wang, Li-San and Ruiz, Agustin and van Duijn, Cornelia M and Holmans, Peter A and Seshadri, Sudha and Williams, Julie and Amouyel, Phillippe and Schellenberg, Gerard D and Lambert, Jean-Charles and Pericak-Vance, Margaret A} } @article {8048, title = {The role of functional status on the relationship between blood pressure and cognitive decline: the Cardiovascular Health Study.}, journal = {J Hypertens}, year = {2019}, month = {2019 May 01}, abstract = {

OBJECTIVE: To examine whether self-reported functional status modified the association between blood pressure (BP) and cognitive decline among older adults.

METHODS: The study included 2097 US adults aged 75 years and older from the Cardiovascular Health Study, followed for up to 6 years. Functional status was ascertained by self-reported limitation in activities of daily living (ADL; none vs. any). Cognitive function was assessed by the Modified Mini Mental State Exam (3MSE). We used linear mixed models to examine whether the presence of at least one ADL limitation modified the association between BP and cognitive decline. Potential confounders included demographics, physiologic measures, antihypertensive medication use and apolipoprotein E ε4 allele. We conducted stratified analyses for significant interactions between BP and ADL.

RESULTS: The association between BP and change in 3MSE differed by baseline ADL limitation. Among participants without ADL limitation, elevated systolic BP (>=140 mmHg) was associated with a 0.15 decrease (95\% CI -0.24 to -0.07); P value for interaction less than 0.001, whereas in those with an ADL limitation, elevated systolic BP was independently associated with a 0.30 increase in 3MSE scores per year (95\% CI 0.06-0.55). Elevated diastolic BP (>=80 mmHg) was associated with an increase in cognitive function in both groups, although the increase was greater in those with ADL limitation (0.47 points per year vs. 0.18 points per year, P value for interaction = 0.01).

CONCLUSION: Elevated BP appears to be associated with a decrease in cognitive scores among functioning older adults, and modest improvements in cognitive function among poorly functioning elders.

}, issn = {1473-5598}, doi = {10.1097/HJH.0000000000002102}, author = {Miller, Lindsay M and Peralta, Carmen A and Fitzpatrick, Annette L and Wu, Chenkai and Psaty, Bruce M and Newman, Anne B and Odden, Michelle C} } @article {8282, title = {Association of Leukocyte Telomere Length With Mortality Among Adult Participants in 3 Longitudinal Studies.}, journal = {JAMA Netw Open}, volume = {3}, year = {2020}, month = {2020 Feb 05}, pages = {e200023}, abstract = {

Importance: Leukocyte telomere length (LTL) is a trait associated with risk of cardiovascular disease and cancer, the 2 major disease categories that largely define longevity in the United States. However, it remains unclear whether LTL is associated with the human life span.

Objective: To examine whether LTL is associated with the life span of contemporary humans.

Design, Setting, and Participants: This cohort study included 3259 adults of European ancestry from the Cardiovascular Health Study (CHS), Framingham Heart Study (FHS), and Women{\textquoteright}s Health Initiative (WHI). Leukocyte telomere length was measured in 1992 and 1997 in the CHS, from 1995 to 1998 in the FHS, and from 1993 to 1998 in the WHI. Data analysis was conducted from February 2017 to December 2019.

Main Outcomes and Measures: Death and LTL, measured by Southern blots of the terminal restriction fragments, were the main outcomes. Cause of death was adjudicated by end point committees.

Results: The analyzed sample included 3259 participants (2342 [71.9\%] women), with a median (range) age of 69.0 (50.0-98.0) years at blood collection. The median (range) follow-up until death was 10.9 (0.2-23.0) years in CHS, 19.7 (3.4-23.0) years in FHS, and 16.6 (0.5-20.0) years in WHI. During follow-up, there were 1525 deaths (482 [31.6\%] of cardiovascular disease; 373 [24.5\%] of cancer, and 670 [43.9\%] of other or unknown causes). Short LTL, expressed in residual LTL, was associated with increased mortality risk. Overall, the hazard ratio for all-cause mortality for a 1-kilobase decrease in LTL was 1.34 (95\% CI, 1.21-1.47). This association was stronger for noncancer causes of death (cardiovascular death: hazard ratio, 1.28; 95\% CI, 1.08-1.52; cancer: hazard ratio, 1.13; 95\% CI, 0.93-1.36; and other causes: hazard ratio, 1.53; 95\% CI, 1.32-1.77).

Conclusions and Relevance: The results of this study indicate that LTL is associated with a natural life span limit in contemporary humans.

}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2020.0023}, author = {Arbeev, Konstantin G and Verhulst, Simon and Steenstrup, Troels and Kark, Jeremy D and Bagley, Olivia and Kooperberg, Charles and Reiner, Alexander P and Hwang, Shih-Jen and Levy, Daniel and Fitzpatrick, Annette L and Christensen, Kaare and Yashin, Anatoliy I and Aviv, Abraham} } @article {8632, title = {Coagulation factor VIII, white matter hyperintensities and cognitive function: Results from the Cardiovascular Health Study.}, journal = {PLoS One}, volume = {15}, year = {2020}, month = {2020}, pages = {e0242062}, abstract = {

OBJECTIVE: To investigate the relationship between high FVIII clotting activity (FVIII:C), MRI-defined white matter hyperintensities (WMH) and cognitive function over time.

METHODS: Data from the population-based Cardiovascular Health Study (n = 5,888, aged >=65) were used. FVIII:C was measured in blood samples taken at baseline. WMH burden was assessed on two cranial MRI scans taken roughly 5 years apart. Cognitive function was assessed annually using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Test (DSST). We used ordinal logistic regression models adjusted for demographic and cardiovascular factors in cross-sectional and longitudinal WMH analyses, and adjusted linear regression and linear mixed models in the analyses of cognitive function.

RESULTS: After adjustment for confounding, higher levels of FVIII:C were not strongly associated with the burden of WMH on the initial MRI scan (OR>p75 = 1.20, 95\% CI 0.99-1.45; N = 2,735) nor with WMH burden worsening over time (OR>p75 = 1.18, 95\% CI 0.87-1.59; N = 1,527). High FVIII:C showed no strong association with cognitive scores cross-sectionally (3MSE>p75 β = -0.06, 95\%CI -0.45 to 0.32, N = 4,005; DSST>p75 β = -0.69, 95\%CI -1.52 to 0.13, N = 3,954) or over time (3MSE>p75 β = -0.07,95\% CI -0.58 to 0.44, N = 2,764; DSST>p75 β = -0.22, 95\% CI -0.97 to 0.53, N = 2,306) after confounding adjustment.

INTERPRETATION: The results from this cohort study of older adult participants indicate no strong relationships between higher FVIII:C levels and WMH burden or cognitive function in cross-sectional and longitudinal analyses.

}, keywords = {Aged, Blood Coagulation, Cognition, Cross-Sectional Studies, Factor VIII, Female, Humans, Logistic Models, Longitudinal Studies, Magnetic Resonance Imaging, Male, Mental Status and Dementia Tests, Up-Regulation, White Matter}, issn = {1932-6203}, doi = {10.1371/journal.pone.0242062}, author = {Rohmann, Jessica L and Longstreth, W T and Cushman, Mary and Fitzpatrick, Annette L and Heckbert, Susan R and Rice, Kenneth and Rosendaal, Frits R and Sitlani, Colleen M and Psaty, Bruce M and Siegerink, Bob} } @article {8478, title = {Non-esterified fatty acids and telomere length in older adults: The Cardiovascular Health Study.}, journal = {Metabol Open}, volume = {8}, year = {2020}, month = {2020 Dec}, pages = {100058}, abstract = {

Background: Telomeres shorten as organisms age, placing limits on cell proliferation and serving as a marker of biological aging. Non-esterified fatty acids (NEFAs) are a key mediator of age-related metabolic abnormalities. We aimed to determine if NEFAs are associated with telomere length in community-living older adults.

Material and methods: We cross-sectionally studied 1648 participants of the Cardiovascular Health Study (CHS) who underwent concomitant telomere length measurement from a sample of 4715 participants who underwent measurement of circulating total fasting NEFAs in stored specimens from their 1992-3 clinic visit. We used linear regression and inverse probability weighting to model telomere length as a function of NEFAs with adjustment for age, gender, race, clinic, BMI, marital status, smoking status, alcohol intake, diabetes status, years of education, hypertension status, prevalent cardiovascular disease, C-reactive protein, total adiponectin, albumin, fetuin-A, fasting insulin, eGFR, total cholesterol, HDL-cholesterol, triglycerides, and general health status.

Results: Higher NEFAs were significantly associated with shorter telomere length, after adjusting for age, gender, race, and clinic site (β~=~-0.034; SE~=~0.015; ~=~0.02). Estimates remained similar in fully adjusted models where each SD of NEFA increment was associated with 0.042 kilobase (kb) pairs shorter telomere length (standard error~=~0.016; ~=~0.007); for comparison the coefficient for a single year of age in the same model was~-0.017. These results were similar in strata of sex, and waist circumference although they tended to be strongest among participants in the youngest tertile of age (β~=~-0.079; SE~=~0.029; P~=~0.01).

Conclusions: In this population-based cohort of community-living elders, we observed a significant inverse association between NEFAs and telomere length. If confirmed, NEFAs may represent a promising target for interventions to slow biological aging.

}, issn = {2589-9368}, doi = {10.1016/j.metop.2020.100058}, author = {Ahiawodzi, Peter and Fitzpatrick, Annette L and Djouss{\'e}, Luc and Ix, Joachim H and Kizer, Jorge R and Mukamal, Kenneth J} } @article {8399, title = {Sex Differences in the Association Between Pentraxin 3 and Cognitive Decline: The Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {75}, year = {2020}, month = {2020 Jul 13}, pages = {1523-1529}, abstract = {

BACKGROUND: The importance of systemic inflammation, measured by C-reactive protein, in cognitive decline has been demonstrated; however, the role of vascular inflammation is less understood. Pentraxin 3 (PTX3) is a novel marker of vascular inflammation.

METHODS: We followed adults 65 and older, free of cardiovascular disease (CVD) for up to 9 years (n = 1,547) in the Cardiovascular Health Study. We evaluated the relationship between PTX3 and change in cognitive function, measured using the Modified Mini-Mental State Examination (3MSE), and incident cognitive impairment (3MSE < 80). Mediation by CVD events, and effect modification by sex and apolipoprotein E ɛ4 allele (APOE4) were also examined.

RESULTS: The average decline in 3MSE was 0.77 points per year. The association between PTX3 and change in 3MSE differed between women and men (p = .02). In the adjusted model, each standard deviation higher in PTX3 was associated with a 0.20 greater decline in 3MSE score per year in women over follow-up (95\% CI: -0. 37, -0.03; p = .02), compared to no change in men (β = 0.07; 95\% CI: -0.08, 0.22). CVD events had a minor effect on the associations. No effect modification by APOE4 was found, although we observed the association of PTX3 and cognitive impairment in women was attenuated and nonsignificant after adjustment for APOE4. There was a paradoxical protective association between PTX3 and reduced cognitive impairment in men, even after adjustment for APOE4.

CONCLUSIONS: We found that vascular inflammation was significantly associated with cognitive decline in older women, but not men.

}, issn = {1758-535X}, doi = {10.1093/gerona/glz217}, author = {Miller, Lindsay M and Jenny, Nancy S and Rawlings, Andreea M and Arnold, Alice M and Fitzpatrick, Annette L and Lopez, Oscar L and Odden, Michelle C} } @article {8988, title = {Association of low-frequency and rare coding variants with information processing speed.}, journal = {Transl Psychiatry}, volume = {11}, year = {2021}, month = {2021 12 04}, pages = {613}, abstract = {

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67\%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 {\texttimes} 10) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

}, keywords = {Adult, Aging, Cognition, Genome-Wide Association Study, Geroscience, Humans, Polymorphism, Single Nucleotide, Ubiquitin-Protein Ligases}, issn = {2158-3188}, doi = {10.1038/s41398-021-01736-6}, author = {Bressler, Jan and Davies, Gail and Smith, Albert V and Saba, Yasaman and Bis, Joshua C and Jian, Xueqiu and Hayward, Caroline and Yanek, Lisa and Smith, Jennifer A and Mirza, Saira S and Wang, Ruiqi and Adams, Hieab H H and Becker, Diane and Boerwinkle, Eric and Campbell, Archie and Cox, Simon R and Eiriksdottir, Gudny and Fawns-Ritchie, Chloe and Gottesman, Rebecca F and Grove, Megan L and Guo, Xiuqing and Hofer, Edith and Kardia, Sharon L R and Knol, Maria J and Koini, Marisa and Lopez, Oscar L and Marioni, Riccardo E and Nyquist, Paul and Pattie, Alison and Polasek, Ozren and Porteous, David J and Rudan, Igor and Satizabal, Claudia L and Schmidt, Helena and Schmidt, Reinhold and Sidney, Stephen and Simino, Jeannette and Smith, Blair H and Turner, Stephen T and van der Lee, Sven J and Ware, Erin B and Whitmer, Rachel A and Yaffe, Kristine and Yang, Qiong and Zhao, Wei and Gudnason, Vilmundur and Launer, Lenore J and Fitzpatrick, Annette L and Psaty, Bruce M and Fornage, Myriam and Arfan Ikram, M and van Duijn, Cornelia M and Seshadri, Sudha and Mosley, Thomas H and Deary, Ian J} } @article {8997, title = {Association of mitochondrial DNA copy number with cardiometabolic diseases.}, journal = {Cell Genom}, volume = {1}, year = {2021}, month = {2021 Oct 13}, abstract = {

Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: among younger participants (<65 years of age), each additional 10 years of age was associated with 0.03 standard deviation (s.d.) higher level of mtDNA CN ( = 0.0014) versus a 0.14 s.d. lower level of mtDNA CN ( = 1.82 {\texttimes} 10) among older participants (>=65 years). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity ( = 5.6 {\texttimes} 10), hypertension ( = 2.8 {\texttimes} 10), diabetes ( = 3.6 {\texttimes} 10), and hyperlipidemia ( = 6.3 {\texttimes} 10). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.

}, issn = {2666-979X}, doi = {10.1016/j.xgen.2021.100006}, author = {Liu, Xue and Longchamps, Ryan J and Wiggins, Kerri L and Raffield, Laura M and Bielak, Lawrence F and Zhao, Wei and Pitsillides, Achilleas and Blackwell, Thomas W and Yao, Jie and Guo, Xiuqing and Kurniansyah, Nuzulul and Thyagarajan, Bharat and Pankratz, Nathan and Rich, Stephen S and Taylor, Kent D and Peyser, Patricia A and Heckbert, Susan R and Seshadri, Sudha and Cupples, L Adrienne and Boerwinkle, Eric and Grove, Megan L and Larson, Nicholas B and Smith, Jennifer A and Vasan, Ramachandran S and Sofer, Tamar and Fitzpatrick, Annette L and Fornage, Myriam and Ding, Jun and Correa, Adolfo and Abecasis, Goncalo and Psaty, Bruce M and Wilson, James G and Levy, Daniel and Rotter, Jerome I and Bis, Joshua C and Satizabal, Claudia L and Arking, Dan E and Liu, Chunyu} } @article {8710, title = {Balance and cognitive decline in older adults in the cardiovascular health study.}, journal = {Age Ageing}, year = {2021}, month = {2021 Mar 10}, abstract = {

BACKGROUND: Previous studies have demonstrated an association between gait speed and cognitive function. However, the relationship between balance and cognition remains less well explored. This study examined the cross-sectional and longitudinal relationship of balance and cognitive decline in older adults.

METHODS: A cohort of 4,811 adults, aged >=65~years, participating in the Cardiovascular Health Study was followed for 6~years. Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Test (DSST) were used to measure cognition. Tandem balance measures were used to evaluate balance. Regression models were adjusted for demographics, behavioural and disease factors.

RESULTS: Worse balance was independently associated with worse cognition in cross-sectional analysis. Longitudinally, participants aged >=76~years with poorer balance had a faster rate of decline after adjustment for co-variates: -0.97 points faster decline in 3MSE per year (95\% confidence interval (CI): -1.32, -0.63) compared to the participants with good balance. There was no association of balance and change in 3MSE among adults aged <76~years (P value for balance and age interaction < 0.0001). DSST scores reflected -0.21 (95\% CI: -0.37, -0.05) points greater decline when adjusted for co-variates. In Cox proportional hazard models, participants with worse balance had a higher risk of being cognitively impaired over the 6 years of follow-up visits (adjusted HR:1.72, 95\% CI: 1.30, 2.29).

CONCLUSIONS: Future studies should evaluate standing balance as a potential screening technique to identify individuals at risk of cognitive decline. Furthermore, a better understanding of the pathophysiological link between balance and cognition may inform strategies to prevent cognitive decline.

}, issn = {1468-2834}, doi = {10.1093/ageing/afab038}, author = {Meunier, Claire C and Smit, Ellen and Fitzpatrick, Annette L and Odden, Michelle C} } @article {8793, title = {Body mass index in early adulthood and dementia in late life: Findings from a pooled cohort.}, journal = {Alzheimers Dement}, year = {2021}, month = {2021 May 13}, abstract = {

INTRODUCTION: To examine the independent association of body mass index (BMI) in early adulthood with dementia incidence among men and women.

METHODS: We studied 5104 older adults from the Cardiovascular Health Study (CHS) and the Health, Aging, and Body Composition (Health ABC) study. We imputed early adulthood and midlife BMI using a pooled parent cohort with complete adult lifespan coverage and previously established methods. Dementia was ascertained using criteria such as neuropsychological test battery, medical records, and dementia-related drug use. Pooled logistic regression (PLR) models were used.

RESULTS: Compared to women with normal BMI in early adulthood, the odds of dementia were higher among both overweight (odds ratio [OR]~=~1.8; 95\% confidence interval [CI]~=~1.31 to 2.54) and obese (OR~=~2.45; 95\% CI~=~1.47 to 4.06) women, independent of mid- and late-life BMI. Similar relationship was observed in men.

CONCLUSIONS: With the growing obesity epidemic among US adults, efforts aimed at reducing dementia may need to begin obesity prevention and treatment early in the life course.

}, issn = {1552-5279}, doi = {10.1002/alz.12367}, author = {Zeki Al Hazzouri, Adina and Vittinghoff, Eric and Hoang, Tina and Golden, Sherita H and Fitzpatrick, Annette L and Zhang, Adina and Grasset, Leslie and Yaffe, Kristine} } @article {8987, title = {Depressive Symptoms Imputed Across the Life Course Are Associated with Cognitive Impairment and Cognitive Decline.}, journal = {J Alzheimers Dis}, volume = {83}, year = {2021}, month = {2021}, pages = {1379-1389}, abstract = {

BACKGROUND: Depressive symptoms may increase risk for dementia, but findings are controversial because late-life depression may be a prodromal dementia symptom. Life course data on depression and dementia risk may clarify this association; however, data is limited.

OBJECTIVE: To impute adult depressive symptoms trajectories across adult life stages and estimate the association with cognitive impairment and decline.

METHODS: Using a pooled study of 4 prospective cohorts (ages 20-89), we imputed adult life course depressive symptoms trajectories based on Center for Epidemiologic Studies Depression Scale-10 (CESD-10) and calculated time-weighted averages for early adulthood (ages 20-49), mid-life (ages 50-69), and late-life (ages 70-89) for 6,122 older participants. Adjusted pooled logistic and mixed-effects models estimated associations of imputed depressive symptoms with two cognitive outcomes: cognitive impairment defined by established criteria and a composite cognitive score.

RESULTS: In separate models, elevated depressive symptoms in each life stage were associated with cognitive outcomes: early adulthood OR for cognitive impairment = 1.59 (95\%CI: 1.35,1.87); mid-life OR = 1.94 (95\%CI:1.16, 3.26); and late-life OR = 1.77 (95\%CI:1.42, 2.21). When adjusted for depressive symptoms in the other life-stages, elevated depressive symptoms in early adulthood (OR = 1.73; 95\%CI: 1.42,2.11) and late-life (OR = 1.43; 95\%CI: 1.08,1.89) remained associated with cognitive impairment and were also associated with faster rates of cognitive decline (p < 0.05).

CONCLUSION: Imputing depressive symptom trajectories from pooled cohorts may help expand data across the life course. Our findings suggest early adulthood depressive symptoms may be a risk factor for cognitive impairment independent of mid- or late-life depressive symptoms.

}, keywords = {Adult, Aged, Aged, 80 and over, Aging, Cognitive Dysfunction, Cohort Studies, Dementia, Depression, Female, Humans, Male, Middle Aged, Prodromal Symptoms, Risk Factors}, issn = {1875-8908}, doi = {10.3233/JAD-210588}, author = {Brenowitz, Willa D and Zeki Al Hazzouri, Adina and Vittinghoff, Eric and Golden, Sherita H and Fitzpatrick, Annette L and Yaffe, Kristine} } @article {8921, title = {Egg consumption, overall diet quality, and risk of type 2 diabetes and coronary heart disease: A pooling project of US prospective cohorts.}, journal = {Clin Nutr}, volume = {40}, year = {2021}, month = {2021 05}, pages = {2475-2482}, abstract = {

BACKGROUND AND AIMS: Data on the relation of egg consumption with risk of type 2 diabetes (T2D) and coronary heart disease (CHD) are limited and inconsistent. Few studies have controlled for overall dietary patterns in egg-T2D or egg-CHD analyses, and it is unclear whether any observed elevated risks of T2D and CHD with frequent egg consumption is real or due to confounding by dietary habits. We tested the hypothesis that frequent egg consumption is associated with a higher risk of T2D and CHD risk after adjustment for overall dietary patterns among adults.

DESIGN: We used prospective cohort design to complete time-to-event analyses.

METHODS: We pooled de novo, harmonized, individual-level analyses from nine US cohorts (n~=~103,811). Cox regression was used to estimate hazard ratios separately in each cohort adjusting for age, ethnicity, body mass index (BMI), exercise, smoking, alcohol intake, and dietary patterns. We pooled cohort-specific results using an inverse-variance weighted method to estimate summary relative risks.

RESULTS: Median age ranged from 25 to 72 years. Median egg consumption was 1 egg per week in most of the cohorts. While egg consumption up to one per week was not associated with T2D risk, consumption of >=2 eggs per week was associated with elevated risk [27\% elevated risk of T2D comparing 7+ eggs/week with none (95\% CI: 16\%-37\%)]. There was little evidence for heterogeneity across cohorts and we observed similar conclusions when stratified by BMI. Overall, egg consumption was not associated with the risk of CHD. However, in a sensitivity analysis, there was a 30\% higher risk of CHD (95\% CI: 3\%-56\%) restricted to older adults consuming 5-6 eggs/week.

CONCLUSIONS: Our data showed an elevated risk of T2D with egg consumption of >=2 eggs per week but not with <2 eggs/week. While there was no overall association of egg consumption with CHD risk, the elevated CHD observed with consumption of 5-6 eggs/week in older cohorts merits further investigation.

}, keywords = {Adult, Aged, Cohort Studies, Coronary Disease, Diabetes Mellitus, Type 2, Diet, Eggs, Humans, Middle Aged, Prospective Studies, Risk Factors, United States}, issn = {1532-1983}, doi = {10.1016/j.clnu.2021.03.003}, author = {Djouss{\'e}, Luc and Zhou, Guohai and McClelland, Robyn L and Ma, Nanxun and Zhou, Xia and Kabagambe, Edmond K and Talegawkar, Sameera A and Judd, Suzanne E and Biggs, Mary L and Fitzpatrick, Annette L and Clark, Cheryl R and Gagnon, David R and Steffen, Lyn M and Gaziano, J Michael and Lee, I-Min and Buring, Julie E and Manson, JoAnn E} } @article {8912, title = {HDL (High-Density Lipoprotein) Subspecies, Prevalent Covert Brain Infarcts, and Incident Overt Ischemic Stroke: Cardiovascular Health Study.}, journal = {Stroke}, year = {2021}, month = {2021 Oct 14}, pages = {STROKEAHA121034299}, abstract = {

BACKGROUND AND PURPOSE: Whether HDL (high-density lipoprotein) is associated with risk of vascular brain injury is unclear. HDL is comprised of many apo (apolipoprotein) species, creating distinct subtypes of HDL.

METHODS: We utilized sandwich ELISA to determine HDL subspecies from plasma collected in 1998/1999 from 2001 CHS (Cardiovascular Health Study) participants (mean age, 80 years).

RESULTS: In cross-sectional analyses, participants with higher apoA1 in plasma and lower apoE in HDL were less likely to have prevalent covert magnetic resonance imaging-defined infarcts: odds ratio for apoA1 Q4 versus Q1, 0.68 (95\% CI, 0.50-0.93), and odds ratio for apoE Q4 versus Q1, 1.36 (95\% CI, 1.01-1.84). Similarly, apoA1 in the subspecies of HDL that lacked apoC3, apoJ, or apoE was inversely related to covert infarcts, and apoE in the subspecies of HDL that lacked apoC3 or apoJ was directly related to covert infarcts in prospective analyses. In contrast, the concentrations of apoA1 and apoE in the complementary subspecies of HDL that contained these apos were unrelated to covert infarcts. Patterns of associations between incident overt ischemic stroke and apoA1, apoE, and apoA1 and apoE in subspecies of HDL were similar to those observed for covert infarcts but less pronounced.

CONCLUSIONS: This study highlights HDL subspecies defined by apo content as relevant biomarkers of covert and overt vascular brain injury.

}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.121.034299}, author = {Koch, Manja and Aroner, Sarah A and Fitzpatrick, Annette L and Longstreth, W T and Furtado, Jeremy D and Mukamal, Kenneth J and Jensen, Majken K} } @article {8708, title = {Ophthalmic conditions associated with dementia risk: The Cardiovascular Health Study.}, journal = {Alzheimers Dement}, year = {2021}, month = {2021 Mar 31}, abstract = {

INTRODUCTION: Ophthalmic conditions and dementia appear to overlap and may share common pathways, but research has not differentiated dementia subtypes.

METHODS: Diagnoses of cataracts, age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma were based on medical histories and International Classification of Diseases, Ninth Revision (ICD-9) codes for 3375 participants from the Cardiovascular Health Study. Dementia, including Alzheimer{\textquoteright}s disease (AD) and vascular dementia (VaD), was classified using standardized research criteria.

RESULTS: Cataracts were associated with AD (hazard ratio [HR]~=~1.34; 95\% confidence interval [CI]~=~1.01-1.80) and VaD/mixed dementia (HR~=~1.41; 95\% CI~=~1.02-1.95). AMD was associated with AD only (HR~=~1.87; 95\% CI~=~1.13-3.09), whereas DR was associated with VaD/mixed dementia only (HR~=~2.63; 95\% CI~=~1.10-6.27).

DISCUSSION: Differential associations between specific ophthalmic conditions and dementia subtypes may elucidate pathophysiologic pathways. Lack of association between glaucoma and dementia was most surprising from these analyses.

}, issn = {1552-5279}, doi = {10.1002/alz.12313}, author = {Hwang, Phillip H and Longstreth, Will T and Thielke, Stephen M and Francis, Courtney E and Carone, Marco and Kuller, Lewis H and Fitzpatrick, Annette L} } @article {8704, title = {Serum Individual Nonesterified Fatty Acids and Risk of Heart Failure in Older Adults.}, journal = {Cardiology}, year = {2021}, month = {2021 Feb 25}, pages = {1-8}, abstract = {

BACKGROUND: Heart failure (HF) is highly prevalent among older adults and is associated with high costs. Although serum total nonesterified fatty acids (NEFAs) have been positively associated with HF risk, the contribution of each individual NEFA to HF risk has not been examined.

OBJECTIVE: The aim of this study was to examine the association of individual fasting NEFAs with HF risk in older adults.

METHODS: In this prospective cohort study of older adults, we measured 35 individual NEFAs in 2,140 participants of the Cardiovascular Health Study using gas chromatography. HF was ascertained using review of medical records by an endpoint committee.

RESULTS: The mean age was 77.7 {\textpm} 4.4 years, and 38.8\% were male. During a median follow-up of 9.7 (maximum 19.0) years, 655 new cases of HF occurred. In a multivariable Cox regression model controlling for demographic and anthropometric variables, field center, education, serum albumin, glomerular filtration rate, physical activity, alcohol consumption, smoking, hormone replacement therapy, unintentional weight loss, and all other measured NEFAs, we observed inverse associations (HR [95\% CI] per standard deviation) of nonesterified pentadecanoic (15:0) (0.73 [0.57-0.94]), γ-linolenic acid (GLA) (0.87 [0.75-1.00]), and docosahexaenoic acid (DHA) (0.73 [0.61-0.88]) acids with HF, and positive associations of nonesterified stearic (18:0) (1.30 [1.04-1.63]) and nervonic (24:1n-9) (1.17 [1.06-1.29]) acids with HF.

CONCLUSION: Our data are consistent with a higher risk of HF with nonesterified stearic and nervonic acids and a lower risk with nonesterified 15:0, GLA, and DHA in older adults. If confirmed in other studies, specific NEFAs may provide new targets for HF prevention.

}, issn = {1421-9751}, doi = {10.1159/000513917}, author = {Djouss{\'e}, Luc and Biggs, Mary L and Matthan, Nirupa R and Ix, Joachim H and Fitzpatrick, Annette L and King, Irena and Lemaitre, Rozenn N and McKnight, Barbara and Kizer, Jorge R and Lichtenstein, Alice H and Mukamal, Kenneth J and Siscovick, David S} } @article {9252, title = {CD133 as a Biomarker for an Autoantibody-to-ImmunoPET Paradigm for the Early Detection of Small Cell Lung Cancer.}, journal = {J Nucl Med}, volume = {63}, year = {2022}, month = {2022 Nov}, pages = {1701-1707}, abstract = {

Small cell lung cancer (SCLC) is a deadly neuroendocrine tumor for which there are no screening methods sensitive enough to facilitate early, effective intervention. We propose targeting the neuroendocrine tumor neoantigen CD133 via antibody-based early detection and PET (immunoPET) to facilitate earlier and more accurate detection of SCLC. RNA sequencing datasets, immunohistochemistry, flow cytometry, and Western blots were used to quantify CD133 expression in healthy and SCLC patients. CD133 was imaged using near-infrared fluorescence (NIRF) immunoimaging, and Zr immunoPET. Anti(α)-CD133 autoantibody levels were measured in SCLC patient plasma using antibody microarrays. Across 6 publicly available datasets, CD133 messenger RNA was found to be higher in SCLC tumors than in other tissues, including healthy or normal adjacent lung and non-SCLC samples. Critically, the upregulation of CD133 messenger RNA in SCLC was associated with a significant increase (hazard ratio, 2.62) in death. CD133 protein was expressed in primary human SCLC, in SCLC patient-derived xenografts, and in both SCLC cell lines tested (H82 and H69). Using an H82 xenograft mouse model, we first imaged CD133 expression with NIRF. Both and NIRF clearly showed that a fluorophore-tagged αCD133 homed to lung tumors. Next, we validated the noninvasive visualization of subcutaneous and orthotopic H82 xenografts via immunoPET. An αCD133 antibody labeled with the positron-emitting radiometal Zr demonstrated significant accumulation in tumor tissue while producing minimal uptake in healthy organs. Finally, plasma αCD133 autoantibodies were found in subjects from cohort studies up to 1 year before SCLC diagnosis. In light of these findings, we conclude that the presence of αCD133 autoantibodies in a blood sample followed by CD133-targeted Zr-immunoPET could be an effective early detection screening strategy for SCLC.

}, keywords = {Animals, Autoantibodies, Biomarkers, Cell Line, Tumor, Disease Models, Animal, Early Detection of Cancer, Humans, Lung Neoplasms, Mice, Mice, Nude, Neuroendocrine Tumors, Positron-Emission Tomography, RNA, Messenger, Small Cell Lung Carcinoma}, issn = {1535-5667}, doi = {10.2967/jnumed.121.263511}, author = {Kunihiro, Andrew G and Sarrett, Samantha M and Lastwika, Kristin J and Solan, Joell L and Pisarenko, Tatyana and Kein{\"a}nen, Outi and Rodriguez, Cindy and Taverne, Lydia R and Fitzpatrick, Annette L and Li, Christopher I and Houghton, A McGarry and Zeglis, Brian M and Lampe, Paul D} } @article {9169, title = {Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning.}, journal = {Mol Psychiatry}, year = {2022}, month = {2022 Aug 16}, abstract = {

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

}, issn = {1476-5578}, doi = {10.1038/s41380-022-01710-8}, author = {Lahti, Jari and Tuominen, Samuli and Yang, Qiong and Pergola, Giulio and Ahmad, Shahzad and Amin, Najaf and Armstrong, Nicola J and Beiser, Alexa and Bey, Katharina and Bis, Joshua C and Boerwinkle, Eric and Bressler, Jan and Campbell, Archie and Campbell, Harry and Chen, Qiang and Corley, Janie and Cox, Simon R and Davies, Gail and De Jager, Philip L and Derks, Eske M and Faul, Jessica D and Fitzpatrick, Annette L and Fohner, Alison E and Ford, Ian and Fornage, Myriam and Gerring, Zachary and Grabe, Hans J and Grodstein, Francine and Gudnason, Vilmundur and Simonsick, Eleanor and Holliday, Elizabeth G and Joshi, Peter K and Kajantie, Eero and Kaprio, Jaakko and Karell, Pauliina and Kleineidam, Luca and Knol, Maria J and Kochan, Nicole A and Kwok, John B and Leber, Markus and Lam, Max and Lee, Teresa and Li, Shuo and Loukola, Anu and Luck, Tobias and Marioni, Riccardo E and Mather, Karen A and Medland, Sarah and Mirza, Saira S and Nalls, Mike A and Nho, Kwangsik and O{\textquoteright}Donnell, Adrienne and Oldmeadow, Christopher and Painter, Jodie and Pattie, Alison and Reppermund, Simone and Risacher, Shannon L and Rose, Richard J and Sadashivaiah, Vijay and Scholz, Markus and Satizabal, Claudia L and Schofield, Peter W and Schraut, Katharina E and Scott, Rodney J and Simino, Jeannette and Smith, Albert V and Smith, Jennifer A and Stott, David J and Surakka, Ida and Teumer, Alexander and Thalamuthu, Anbupalam and Trompet, Stella and Turner, Stephen T and van der Lee, Sven J and Villringer, Arno and V{\"o}lker, Uwe and Wilson, Robert S and Wittfeld, Katharina and Vuoksimaa, Eero and Xia, Rui and Yaffe, Kristine and Yu, Lei and Zare, Habil and Zhao, Wei and Ames, David and Attia, John and Bennett, David A and Brodaty, Henry and Chasman, Daniel I and Goldman, Aaron L and Hayward, Caroline and Ikram, M Arfan and Jukema, J Wouter and Kardia, Sharon L R and Lencz, Todd and Loeffler, Markus and Mattay, Venkata S and Palotie, Aarno and Psaty, Bruce M and Ramirez, Alfredo and Ridker, Paul M and Riedel-Heller, Steffi G and Sachdev, Perminder S and Saykin, Andrew J and Scherer, Martin and Schofield, Peter R and Sidney, Stephen and Starr, John M and Trollor, Julian and Ulrich, William and Wagner, Michael and Weir, David R and Wilson, James F and Wright, Margaret J and Weinberger, Daniel R and Debette, Stephanie and Eriksson, Johan G and Mosley, Thomas H and Launer, Lenore J and van Duijn, Cornelia M and Deary, Ian J and Seshadri, Sudha and R{\"a}ikk{\"o}nen, Katri} } @article {9095, title = {Longitudinal Changes in Hearing and Visual Impairments and Risk of Dementia in Older Adults in the United States.}, journal = {JAMA Netw Open}, volume = {5}, year = {2022}, month = {2022 05 02}, pages = {e2210734}, abstract = {

Importance: Hearing and vision problems are individually associated with increased dementia risk, but the impact of having concurrent hearing and vision deficits, ie, dual sensory impairment (DSI), on risk of dementia, including its major subtypes Alzheimer disease (AD) and vascular dementia (VaD), is not well known.

Objective: To evaluate whether DSI is associated with incident dementia in older adults.

Design, Setting, and Participants: This prospective cohort study from the Cardiovascular Health Study (CHS) was conducted between 1992 and 1999, with as many as 8 years of follow-up. The multicenter, population-based sample was recruited from Medicare eligibility files in 4 US communities with academic medical centers. Of 5888 participants aged 65 years and older in CHS, 3602 underwent cranial magnetic resonance imaging and completed the modified Mini-Mental State Examination in 1992 to 1994 as part of the CHS Cognition Study. A total of 227 participants were excluded due to prevalent dementia, leaving a total of 3375 participants without dementia at study baseline. The study hypothesis was that DSI would be associated with increased risk of dementia compared with no sensory impairment. The association between the duration of DSI with risk of dementia was also evaluated. Data analysis was conducted from November 2019 to February 2020.

Exposures: Hearing and vision impairments were collected via self-report at baseline and as many as 5 follow-up visits.

Main Outcomes and Measures: All-cause dementia, AD, and VaD, classified by a multidisciplinary committee using standardized criteria.

Results: A total of 2927 participants with information on hearing and vision at all available study visits were included in the analysis (mean [SD] age, 74.6 [4.8] years; 1704 [58.2\%] women; 455 [15.5\%] African American or Black; 2472 [85.5\%] White). Compared with no sensory impairment, DSI was associated with increased risk of all-cause dementia (hazard ratio [HR], 2.60; 95\% CI, 1.66-2.06; P < .001), AD (HR, 3.67; 95\% CI, 2.04-6.60; P < .001) but not VaD (HR, 2.03; 95\% CI, 1.00-4.09; P = .05).

Conclusions and Relevance: In this cohort study, DSI was associated with increased risk of dementia, particularly AD. Evaluation of hearing and vision in older adults may help to identify those at high risk of developing dementia.

}, keywords = {Aged, Alzheimer Disease, Cohort Studies, Female, Hearing, Hearing Loss, Humans, Male, Medicare, Prospective Studies, United States, Vision Disorders}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2022.10734}, author = {Hwang, Phillip H and Longstreth, W T and Thielke, Stephen M and Francis, Courtney E and Carone, Marco and Kuller, Lewis H and Fitzpatrick, Annette L} } @article {9502, title = {Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk.}, journal = {J Am Heart Assoc}, year = {2023}, month = {2023 Oct 07}, pages = {e029090}, abstract = {

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95\% CI, 1.04-1.12; <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; =0.11) or in the reverse direction (β=-0.012; =0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (β=-0.084; <0.001), but the reverse direction was not significant (=0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level (=0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=-0.092; <0.001). Conclusions Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

}, issn = {2047-9980}, doi = {10.1161/JAHA.122.029090}, author = {Liu, Xue and Sun, Xianbang and Zhang, Yuankai and Jiang, Wenqing and Lai, Meng and Wiggins, Kerri L and Raffield, Laura M and Bielak, Lawrence F and Zhao, Wei and Pitsillides, Achilleas and Haessler, Jeffrey and Zheng, Yinan and Blackwell, Thomas W and Yao, Jie and Guo, Xiuqing and Qian, Yong and Thyagarajan, Bharat and Pankratz, Nathan and Rich, Stephen S and Taylor, Kent D and Peyser, Patricia A and Heckbert, Susan R and Seshadri, Sudha and Boerwinkle, Eric and Grove, Megan L and Larson, Nicholas B and Smith, Jennifer A and Vasan, Ramachandran S and Fitzpatrick, Annette L and Fornage, Myriam and Ding, Jun and Carson, April P and Abecasis, Goncalo and Dupuis, Jos{\'e}e and Reiner, Alexander and Kooperberg, Charles and Hou, Lifang and Psaty, Bruce M and Wilson, James G and Levy, Daniel and Rotter, Jerome I and Bis, Joshua C and Satizabal, Claudia L and Arking, Dan E and Liu, Chunyu} } @article {9323, title = {Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts.}, journal = {Neurology}, year = {2023}, month = {2023 Mar 16}, abstract = {

BACKGROUND AND OBJECTIVES: Previous studies suggest lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer{\textquoteright}s disease (AD) and AD related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.

METHODS: We included dementia-free participants from nine diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within {\textpm}5 years (i.e., cross-sectional analyses) or 5 to 20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs. >=60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed Mendelian randomization (MR) analyses to assess causality.

RESULTS: We included up to 19,152 participants (mean age 59 years, 57\% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (Beta=0.04; 95\% CI 0.02, 0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.

DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the US. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000207157}, author = {Zhang, Yuankai and Liu, Xue and Wiggins, Kerri L and Kurniansyah, Nuzulul and Guo, Xiuqing and Rodrigue, Amanda L and Zhao, Wei and Yanek, Lisa R and Ratliff, Scott M and Pitsillides, Achilleas and Aguirre Pati{\~n}o, Juan Sebastian and Sofer, Tamar and Arking, Dan E and Austin, Thomas R and Beiser, Alexa S and Blangero, John and Boerwinkle, Eric and Bressler, Jan and Curran, Joanne E and Hou, Lifang and Hughes, Timothy M and Kardia, Sharon L and Launer, Lenore and Levy, Daniel and Mosley, Tom H and Nasrallah, Ilya M and Rich, Stephen S and Rotter, Jerome I and Seshadri, Sudha and Tarraf, Wassim and Gonz{\'a}lez, Kevin A and Ramachandran, Vasan and Yaffe, Kristine and Nyquist, Paul A and Psaty, Bruce M and DeCarli, Charles S and Smith, Jennifer A and Glahn, David C and Gonz{\'a}lez, Hector M and Bis, Joshua C and Fornage, Myriam and Heckbert, Susan R and Fitzpatrick, Annette L and Liu, Chunyu and Satizabal, Claudia L} } @article {9291, title = {Association of Obesity With Cognitive Decline in Black and White Americans.}, journal = {Neurology}, volume = {100}, year = {2023}, month = {2023 Jan 10}, pages = {e220-e231}, abstract = {

BACKGROUND AND OBJECTIVES: There are disparities in the prevalence of obesity by race, and the relationship between obesity and cognitive decline is unclear. The objective of this study was to determine whether obesity is independently associated with cognitive decline and whether the association between obesity and cognitive decline differs in Black and White adults. We hypothesized that obesity is associated with greater cognitive decline compared with normal weight and that the effect of obesity on cognitive decline is more pronounced in Black adults compared with their White counterparts.

METHODS: We pooled data from 28,867 participants free of stroke and dementia (mean, SD: age 61 [10.7] years at the first cognitive assessment, 55\% female, 24\% Black, and 29\% obese) from 6 cohorts. The primary outcome was the annual change in global cognition. We performed linear mixed-effects models with and without time-varying cumulative mean systolic blood pressure (SBP) and fasting plasma glucose (FPG). Global cognition was set to a t-score metric (mean 50, SD 10) at a participant{\textquoteright}s first cognitive assessment; a 1-point difference represents a 0.1 SD difference in global cognition across the 6 cohorts. The median follow-up was 6.5 years (25th percentile, 75th percentile: 5.03, 20.15).

RESULTS: Obese participants had lower baseline global cognition than normal-weight participants (difference in intercepts, -0.36 [95\% CI, -0.46 to -0.17]; < 0.001). This difference in baseline global cognition was attenuated but was borderline significant after accounting for SBP and FPG (adjusted differences in intercepts, -0.19 [95\% CI, -0.39 to 0.002]; = 0.05). There was no difference in the rate of decline in global cognition between obese and normal-weight participants (difference in slope, 0.009 points/year [95\% CI, -0.009 to 0.03]; = 0.32). After accounting for SBP and FPG, obese participants had a slower decline in global cognition (adjusted difference in slope, 0.03 points/year slower [95\% CI, 0.01 to 0.05]; < 0.001). There was no evidence that race modified the association between body mass index and global cognitive decline ( = 0.34).

DISCUSSION: These results suggest that obesity is associated with lower initial cognitive scores and may potentially attenuate declines in cognition after accounting for BP and FPG.

}, keywords = {Aged, Black or African American, Cognition, Cognitive Dysfunction, Female, Humans, Male, Middle Aged, Obesity, Risk Factors, United States, White}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000201367}, author = {Quaye, Emmanuel and Galecki, Andrzej T and Tilton, Nicholas and Whitney, Rachael and Brice{\~n}o, Emily M and Elkind, Mitchell S V and Fitzpatrick, Annette L and Gottesman, Rebecca F and Griswold, Michael and Gross, Alden L and Heckbert, Susan R and Hughes, Timothy M and Longstreth, W T and Sacco, Ralph L and Sidney, Stephen and Windham, B Gwen and Yaffe, Kristine and Levine, Deborah A} } @article {9238, title = {Neighborhood greenspace and cognition: The cardiovascular health study.}, journal = {Health Place}, volume = {79}, year = {2023}, month = {2023 Jan 03}, pages = {102960}, abstract = {

OBJECTIVES: We examined whether greenspace measures (overall percent greenspace and forest, and number of greenspace types) were associated with clinically adjudicated dementia status.

METHODS: In a sample of non-demented older adults (n~=~2141, average age~=~75.3 years) from the Cardiovascular Health and Cognition Study, Cox proportional hazard and logistic regression analyses were used to estimate associations of baseline greenspace with risks of incident dementia and MCI, respectively, while adjusting for demographics, co-morbidities, and other neighborhood factors. We derived quartiles of percent greenness (greenspace), forest (percent tree canopy cover), and tertiles of greenspace diversity (number of greenspace types) for 5-km radial buffers around participant{\textquoteright}s residences at study entry (1989-1990) from the 1992 National Land Cover Dataset. Dementia status and mild cognitive impairment (MCI) over 10 years was clinically adjudicated.

RESULTS: We observed no significant association between overall percent greenspace and risk of mild cognitive impairment or dementia and mostly null results for forest and greenspace diversity. Forest greenspace was associated with lower odds of MCI (OR quartile 4 versus 1: 0.54, 95\% CI: 0.29-0.98) and greenspace diversity was associated with lower hazard of incident dementia (HR tertile 2 versus 1: 0.70, 95\% CI~=~0.50-0.99).

DISCUSSION: We found divergent results for different types of greenspace and mild cognitive impairment or dementia. Improved greenspace type and diversity measurement could better characterize the association between greenspace and cognition.

}, issn = {1873-2054}, doi = {10.1016/j.healthplace.2022.102960}, author = {Godina, Sara L and Rosso, Andrea L and Hirsch, Jana A and Besser, Lilah M and Lovasi, Gina S and Donovan, Geoffrey H and Garg, Parveen K and Platt, Jonathan M and Fitzpatrick, Annette L and Lopez, Oscar L and Carlson, Michelle C and Michael, Yvonne L} } @article {9289, title = {Posttranslational modifications induce autoantibodies with risk prediction capability in patients with small cell lung cancer.}, journal = {Sci Transl Med}, volume = {15}, year = {2023}, month = {2023 Jan 11}, pages = {eadd8469}, abstract = {

Small cell lung cancer (SCLC) elicits the generation of autoantibodies that result in unique paraneoplastic neurological syndromes. The mechanistic basis for the formation of such autoantibodies is largely unknown but is key to understanding their etiology. We developed a high-dimensional technique that enables detection of autoantibodies in complex with native antigens directly from patient plasma. Here, we used our platform to screen 1009 human plasma samples for 3600 autoantibody-antigen complexes, finding that plasma from patients with SCLC harbors, on average, fourfold higher disease-specific autoantibody signals compared with plasma from patients with other cancers. Across three independent SCLC cohorts, we identified a set of common but previously unknown autoantibodies that are produced in response to both intracellular and extracellular tumor antigens. We further characterized several disease-specific posttranslational modifications within extracellular proteins targeted by these autoantibodies, including citrullination, isoaspartylation, and cancer-specific glycosylation. Because most patients with SCLC have metastatic disease at diagnosis, we queried whether these autoantibodies could be used for SCLC early detection. We created a risk prediction model using five autoantibodies with an average area under the curve of 0.84 for the three cohorts that improved to 0.96 by incorporating cigarette smoke consumption in pack years. Together, our findings provide an innovative approach to identify circulating autoantibodies in SCLC with mechanistic insight into disease-specific immunogenicity and clinical utility.

}, keywords = {Autoantibodies, Humans, Lung Neoplasms, Protein Processing, Post-Translational, Small Cell Lung Carcinoma}, issn = {1946-6242}, doi = {10.1126/scitranslmed.add8469}, author = {Lastwika, Kristin J and Kunihiro, Andrew and Solan, Joell L and Zhang, Yuzheng and Taverne, Lydia R and Shelley, David and Rho, Jung-Hyun and Randolph, Timothy W and Li, Christopher I and Grogan, Eric L and Massion, Pierre P and Fitzpatrick, Annette L and MacPherson, David and Houghton, A McGarry and Lampe, Paul D} } @article {9580, title = {Association analysis of mitochondrial DNA heteroplasmic variants: methods and application.}, journal = {medRxiv}, year = {2024}, month = {2024 Jan 13}, abstract = {

We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α=0.001. Notably, when 5\% or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31\% of African Ancestry, mean age of 62, with 58\% women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on bothpooled samples and within each ancestry group. Our results suggest that mtDNA-Enco ded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the and genes ( <0.001) and advance aging by the Original Burden test. In contrast, SKAT identified significant associations ( <0.001) between diabetes and the aggregated effects of heteroplasmy in several protein-coding genes. Further research is warranted to validate these findings. In summary, our proposed statistical framework represents a valuable tool for facilitating association testing of heteroplasmy with disease traits in large human populations.

}, doi = {10.1101/2024.01.12.24301233}, author = {Sun, Xianbang and Bulekova, Katia and Yang, Jian and Lai, Meng and Pitsillides, Achilleas N and Liu, Xue and Zhang, Yuankai and Guo, Xiuqing and Yong, Qian and Raffield, Laura M and Rotter, Jerome I and Rich, Stephen S and Abecasis, Goncalo and Carson, April P and Vasan, Ramachandran S and Bis, Joshua C and Psaty, Bruce M and Boerwinkle, Eric and Fitzpatrick, Annette L and Satizabal, Claudia L and Arking, Dan E and Ding, Jun and Levy, Daniel and Liu, Chunyu} } @article {9704, title = {Circulating sphingolipids and subclinical brain pathology: the cardiovascular health study.}, journal = {Front Neurol}, volume = {15}, year = {2024}, month = {2024}, pages = {1385623}, abstract = {

BACKGROUND: Sphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults.

METHODS: Brain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40\% male; and 25\% ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP.

RESULTS: In the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [β = 0.05, false-discovery rate corrected () = 0.004 and β = 0.06, = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex ( for interaction = <0.001), such that ceramide d18:1/20:0 associated with higher odds for infarcts in women [OR = 1.26 (95\%CI: 1.07, 1.49), = 0.03]. We did not observe any associations with GFAP blood levels, white matter grade, ventricular grade, mean bilateral hippocampal volume, or total brain volume.

CONCLUSION: Overall, our comprehensive investigation supports the evidence that ceramides and sphingomyelins are associated with increased aging brain pathology and that the direction of association depends on the fatty acid attached to the sphingosine backbone.

}, issn = {1664-2295}, doi = {10.3389/fneur.2024.1385623}, author = {Moseholm, Kristine F and Horn, Jens W and Fitzpatrick, Annette L and Djouss{\'e}, Luc and Longstreth, W T and Lopez, Oscar L and Hoofnagle, Andrew N and Jensen, Majken K and Lemaitre, Rozenn N and Mukamal, Kenneth J} } @article {9743, title = {Circulating sphingolipids in relation to cognitive decline and incident dementia: The Cardiovascular Health Study.}, journal = {Alzheimers Dement (Amst)}, volume = {16}, year = {2024}, month = {2024 Jul-Sep}, pages = {e12623}, abstract = {

INTRODUCTION: Whether circulating levels of sphingolipids are prospectively associated with cognitive decline and dementia risk is uncertain.

METHODS: We measured 14 sphingolipid species in plasma samples from 4488 participants (mean age 76.2 years; 40\% male; and 25\% apolipoprotein E ( ε4 allele carriers). Cognitive decline was assessed annually across 6 years using modified Mini-Mental State Examination (3MSE) and Digital Symbol Substitution Test (DSST). Additionally, a subset of 3050 participants were followed for clinically adjudicated dementia.

RESULTS: Higher plasma levels of sphingomyelin-d18:1/16:0 (SM-16) were associated with a faster cognitive decline measured with 3MSE, in contrast, higher levels of sphingomyelin-d18:1/22:0 (SM-22) were associated with slower decline in cognition measured with DSST. In Cox regression, higher levels of SM-16 (hazard ration [HR]~=~1.24 [95\% confidence interval [CI]: 1.08-1.44]) and ceramide-d18:1/16:0 (Cer-16) (HR~=~1.26 [95\% CI: 1.10-1.45]) were associated with higher risk of incident dementia.

DISCUSSION: Several sphingolipid species appear to be involved in cognitive decline and dementia risk.

HIGHLIGHTS: Plasma levels of sphingolipids were associated with cognitive decline and dementia risk.Ceramides and sphingomyelins with palmitic acid were associated with faster annual cognitive decline and increased risk of dementia.The direction of association depended on the covalently bound saturated fatty acid chain length in analysis of cognitive decline.

}, issn = {2352-8729}, doi = {10.1002/dad2.12623}, author = {Moseholm, Kristine F and Cronj{\'e}, H{\'e}l{\'e}ne T and Koch, Manja and Fitzpatrick, Annette L and Lopez, Oscar L and Otto, Marcia C de Oliveira and Longstreth, W T and Hoofnagle, Andrew N and Mukamal, Kenneth J and Lemaitre, Rozenn N and Jensen, Majken K} } @article {9578, title = {Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance.}, journal = {Alzheimers Res Ther}, volume = {16}, year = {2024}, month = {2024 Jan 20}, pages = {14}, abstract = {

BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia.

METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes.

RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues.

CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

}, keywords = {Aged, Cognition, Genome-Wide Association Study, Humans, Memory, MicroRNAs, Multiomics, Polymorphism, Single Nucleotide}, issn = {1758-9193}, doi = {10.1186/s13195-023-01376-6}, author = {Mei, Hao and Simino, Jeannette and Li, Lianna and Jiang, Fan and Bis, Joshua C and Davies, Gail and Hill, W David and Xia, Charley and Gudnason, Vilmundur and Yang, Qiong and Lahti, Jari and Smith, Jennifer A and Kirin, Mirna and De Jager, Philip and Armstrong, Nicola J and Ghanbari, Mohsen and Kolcic, Ivana and Moran, Christopher and Teumer, Alexander and Sargurupremraj, Murali and Mahmud, Shamsed and Fornage, Myriam and Zhao, Wei and Satizabal, Claudia L and Polasek, Ozren and R{\"a}ikk{\"o}nen, Katri and Liewald, David C and Homuth, Georg and Callisaya, Michele and Mather, Karen A and Windham, B Gwen and Zemunik, Tatijana and Palotie, Aarno and Pattie, Alison and van der Auwera, Sandra and Thalamuthu, Anbupalam and Knopman, David S and Rudan, Igor and Starr, John M and Wittfeld, Katharina and Kochan, Nicole A and Griswold, Michael E and Vitart, Veronique and Brodaty, Henry and Gottesman, Rebecca and Cox, Simon R and Psaty, Bruce M and Boerwinkle, Eric and Chasman, Daniel I and Grodstein, Francine and Sachdev, Perminder S and Srikanth, Velandai and Hayward, Caroline and Wilson, James F and Eriksson, Johan G and Kardia, Sharon L R and Grabe, Hans J and Bennett, David A and Ikram, M Arfan and Deary, Ian J and van Duijn, Cornelia M and Launer, Lenore and Fitzpatrick, Annette L and Seshadri, Sudha and Bressler, Jan and Debette, Stephanie and Mosley, Thomas H} } @article {9913, title = {Circulating non-esterified fatty acids, risk of dementia and cognitive decline: The cardiovascular health study and multi-ethnic study of atherosclerosis.}, journal = {Neurobiol Aging}, volume = {148}, year = {2025}, month = {2025 Apr}, pages = {71-79}, abstract = {

Circulating non-esterified fatty acids (NEFAs) have toxic effects on a variety of organs central to cardiometabolic disease and can cross the blood-brain barrier. Whether NEFAs associate with cognitive decline or dementia remains unknown. Circulating total NEFA levels were measured in 3242 participants without dementia among older adults of the Cardiovascular Health Study (CHS) and related to adjudicated dementia over 6 years (n = 456 cases) and annually assessed cognitive decline. For confirmation, we related circulating NEFAs to cognition assessed 10 years later among 4361 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). In CHS participants, each SD higher NEFA levels were associated with a hazard ratio (HR) for all-cause dementia of 1.11 (95 \% CI: 1.01; 1.22). Baseline NEFA levels were also associated with more rapid decline in cognition over 6 years of follow-up. In MESA, circulating NEFA measurements were associated with lower cognitive scores measured 10 years later.{\textquoteright}

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Cognition, Cognitive Dysfunction, Cohort Studies, Dementia, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Male, Middle Aged, Risk, Risk Factors}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2025.01.009}, author = {Moseholm, Kristine F and Jensen, Majken K and B{\r u}zkov{\'a}, Petra and Aroner, Sarah A and Fitzpatrick, Annette L and Longstreth, W T and Lopez, Oscar and Siscovick, David S and Kizer, Jorge R and Ix, Joachim H and Hughes, Timothy M and Hayden, Kathleen M and Nomura, Sarah and Tsai, Michael Y and McClelland, Robyn and Djouss{\'e}, Luc and Mukamal, Kenneth J} }