@article {617, title = {Estrogen use, APOE, and cognitive decline: evidence of gene-environment interaction.}, journal = {Neurology}, volume = {54}, year = {2000}, month = {2000 May 23}, pages = {1949-54}, abstract = {

OBJECTIVE: APOE-epsilon4 increases the risk of cognitive decline, while elderly women who take estrogen may have less risk of cognitive decline. The authors sought to determine whether estrogen use modifies the association between APOE-epsilon4 and cognitive decline.

METHOD: - As part of the Cardiovascular Health Study, 3,393 Medicare-eligible women (> or =65 years) were randomly selected and recruited from Sacramento County, CA; Washington County, MD; Forsyth County, NC; and Pittsburgh, PA. Cognitive testing was administered annually; the authors studied the 2,716 women with cognitive testing on > or =2 visits. They analyzed change in score on the Modified Mini-Mental State Examination (3MS) as a function of estrogen use, APOE genotype, and baseline common and internal carotid artery wall thickening.

RESULTS: A total of 297 (11\%) women were current estrogen users and 336 (12\%) were past estrogen users. Over the 6-year average follow-up, baseline current users declined 1.5 points on the 3MS whereas never users declined 2.7 points (p = 0.023). Compared with epsilon4-negative women, epsilon4-positive women had a greater adjusted hazard ratio of cognitive impairment (3MS < 80), hazard risk [HR] = 1.47; 95\% CI, 1.13 to 1.90. There was an interaction between estrogen use and epsilon4 presence (p = 0.037). Among epsilon4-negative women, current estrogen use reduced the risk of adjusted cognitive impairment compared with never users by almost half (HR = 0.59; 95\% CI, 0.36 to 0.99), whereas, it did not reduce the risk among epsilon4-positive women (current use, HR = 1.33; 95\% CI, 0.74 to 2.42). Compared with never use, current estrogen use was associated with less internal and common carotid wall thickening in epsilon4-negative women but not in epsilon4-positive women (p for interaction < 0.05 for both). Differences remained after adjusting for age, education, race, and stroke.

CONCLUSIONS: Estrogen use was associated with less cognitive decline among epsilon4-negative women but not epsilon4-positive women. Potential mechanisms, including carotid atherosclerosis, by which epsilon4 may interact with estrogen and cognition warrant further investigation.

}, keywords = {Aged, Alzheimer Disease, Apolipoprotein E4, Apolipoproteins E, Carotid Stenosis, Estrogen Replacement Therapy, Female, Genotype, Humans, Mental Status Schedule, Neuropsychological Tests, Risk Factors}, issn = {0028-3878}, doi = {10.1212/wnl.54.10.1949}, author = {Yaffe, K and Haan, M and Byers, A and Tangen, C and Kuller, L} } @article {1101, title = {Predicting risk of dementia in older adults: The late-life dementia risk index.}, journal = {Neurology}, volume = {73}, year = {2009}, month = {2009 Jul 21}, pages = {173-9}, abstract = {

OBJECTIVE: To develop a late-life dementia risk index that can accurately stratify older adults into those with a low, moderate, or high risk of developing dementia within 6 years.

METHODS: Subjects were 3,375 participants in the Cardiovascular Health Cognition Study without evidence of dementia at baseline. We used logistic regression to identify those factors most predictive of developing incident dementia within 6 years and developed a point system based on the logistic regression coefficients.

RESULTS: Subjects had a mean age of 76 years at baseline; 59\% were women and 15\% were African American. Fourteen percent (n = 480) developed dementia within 6 years. The final late-life dementia risk index included older age (1-2 points), poor cognitive test performance (2-4 points), body mass index <18.5 (2 points), > or =1 apolipoprotein E epsilon4 alleles (1 point), cerebral MRI findings of white matter disease (1 point) or ventricular enlargement (1 point), internal carotid artery thickening on ultrasound (1 point), history of bypass surgery (1 point), slow physical performance (1 point), and lack of alcohol consumption (1 point) (c statistic, 0.81; 95\% confidence interval, 0.79-0.83). Four percent of subjects with low scores developed dementia over 6 years compared with 23\% of subjects with moderate scores and 56\% of subjects with high scores.

CONCLUSIONS: The late-life dementia risk index accurately stratified older adults into those with low, moderate, and high risk of developing dementia. This tool could be used in clinical or research settings to target prevention and intervention strategies toward high-risk individuals.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Alcohol Drinking, Apolipoprotein E4, Body Mass Index, Carotid Stenosis, Cerebrum, Cognition Disorders, Cohort Studies, Coronary Artery Bypass, Dementia, Female, Genetic Markers, Health Status Indicators, Humans, Logistic Models, Male, Predictive Value of Tests, Risk Assessment, Risk Factors, Risk Reduction Behavior}, issn = {1526-632X}, doi = {10.1212/WNL.0b013e3181a81636}, author = {Barnes, D E and Covinsky, K E and Whitmer, R A and Kuller, L H and Lopez, O L and Yaffe, K} } @article {6799, title = {GWAS for executive function and processing speed suggests involvement of the CADM2 gene.}, journal = {Mol Psychiatry}, volume = {21}, year = {2016}, month = {2016 Feb}, pages = {189-97}, abstract = {

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 {\texttimes} 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 {\texttimes} 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 {\texttimes} 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 {\texttimes} 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 {\texttimes} 10(-11)) and neuron cell-cell adhesion (P-value=1.48 {\texttimes} 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

}, issn = {1476-5578}, doi = {10.1038/mp.2015.37}, author = {Ibrahim-Verbaas, C A and Bressler, J and Debette, S and Schuur, M and Smith, A V and Bis, J C and Davies, G and Trompet, S and Smith, J A and Wolf, C and Chibnik, L B and Liu, Y and Vitart, V and Kirin, M and Petrovic, K and Polasek, O and Zgaga, L and Fawns-Ritchie, C and Hoffmann, P and Karjalainen, J and Lahti, J and Llewellyn, D J and Schmidt, C O and Mather, K A and Chouraki, V and Sun, Q and Resnick, S M and Rose, L M and Oldmeadow, C and Stewart, M and Smith, B H and Gudnason, V and Yang, Q and Mirza, S S and Jukema, J W and deJager, P L and Harris, T B and Liewald, D C and Amin, N and Coker, L H and Stegle, O and Lopez, O L and Schmidt, R and Teumer, A and Ford, I and Karbalai, N and Becker, J T and Jonsdottir, M K and Au, R and Fehrmann, R S N and Herms, S and Nalls, M and Zhao, W and Turner, S T and Yaffe, K and Lohman, K and van Swieten, J C and Kardia, S L R and Knopman, D S and Meeks, W M and Heiss, G and Holliday, E G and Schofield, P W and Tanaka, T and Stott, D J and Wang, J and Ridker, P and Gow, A J and Pattie, A and Starr, J M and Hocking, L J and Armstrong, N J and McLachlan, S and Shulman, J M and Pilling, L C and Eiriksdottir, G and Scott, R J and Kochan, N A and Palotie, A and Hsieh, Y-C and Eriksson, J G and Penman, A and Gottesman, R F and Oostra, B A and Yu, L and DeStefano, A L and Beiser, A and Garcia, M and Rotter, J I and N{\"o}then, M M and Hofman, A and Slagboom, P E and Westendorp, R G J and Buckley, B M and Wolf, P A and Uitterlinden, A G and Psaty, B M and Grabe, H J and Bandinelli, S and Chasman, D I and Grodstein, F and R{\"a}ikk{\"o}nen, K and Lambert, J-C and Porteous, D J and Price, J F and Sachdev, P S and Ferrucci, L and Attia, J R and Rudan, I and Hayward, C and Wright, A F and Wilson, J F and Cichon, S and Franke, L and Schmidt, H and Ding, J and de Craen, A J M and Fornage, M and Bennett, D A and Deary, I J and Ikram, M A and Launer, L J and Fitzpatrick, A L and Seshadri, S and van Duijn, C M and Mosley, T H} }