02737nas a2200301 4500008004100000022001400041245008700055210006900142260001300211300001200224490000600236520182600242100002202068700002202090700002002112700002302132700001902155700002102174700002302195700002802218700002102246700002002267700002502287700002402312700002002336710004302356856003602399 2018 eng d a2328-950300aWhole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease.0 aWholeexome sequencing in 20197 persons for rare variants in Alzh c2018 Jul a832-8420 v53 a

Objective: The genetic bases of Alzheimer's disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra-rare variants in Alzheimer's disease, using whole-exome sequencing in 20,197 individuals.

Methods: We used a gene-based collapsing analysis of loss-of-function ultra-rare variants in a case-control study design with data from the Washington Heights-Inwood Columbia Aging Project, the Alzheimer's Disease Sequencing Project and unrelated individuals from the Institute of Genomic Medicine at Columbia University.

Results: We identified 19 cases carrying extremely rare loss-of-function variants among a collection of 6,965 cases and a single loss-of-function variant among 13,252 controls ( = 2.17 × 10; OR: 36.2 [95% CI: 5.8-1493.0]). Age-at-onset was 7 years earlier for patients with qualifying variant compared with noncarriers. No other gene attained a study-wide level of statistical significance, but multiple top-ranked genes, including , and were among candidates for follow-up studies.

Interpretation: This study implicates ultra-rare, loss-of-function variants in as a significant genetic risk factor for Alzheimer's disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimer's disease cases and controls. This is the first investigation to establish a genome-wide statistically significant association between multiple extremely rare loss-of-function variants in and Alzheimer's disease in a large whole-exome study of unrelated cases and controls.

1 aRaghavan, Neha, S1 aBrickman, Adam, M1 aAndrews, Howard1 aManly, Jennifer, J1 aSchupf, Nicole1 aLantigua, Rafael1 aWolock, Charles, J1 aKamalakaran, Sitharthan1 aPetrovski, Slave1 aTosto, Giuseppe1 aVardarajan, Badri, N1 aGoldstein, David, B1 aMayeux, Richard1 aAlzheimer's Disease Sequencing Project uhttps://chs-nhlbi.org/node/781004157nas a2200409 4500008004100000022001400041245009900055210006900154260001600223520291000239100002303149700002003172700002303192700002103215700002403236700002703260700002303287700002303310700002303333700002003356700002603376700002303402700002103425700002003446700002603466700002203492700001903514700002303533700002003556700002003576700002003596700002303616700002403639700002403663700002403687856003603711 2020 eng d a2168-615700aAssociation Between Blood Pressure and Later-Life Cognition Among Black and White Individuals.0 aAssociation Between Blood Pressure and LaterLife Cognition Among c2020 Apr 133 a

Importance: Black individuals are more likely than white individuals to develop dementia. Whether higher blood pressure (BP) levels in black individuals explain differences between black and white individuals in dementia risk is uncertain.

Objective: To determine whether cumulative BP levels explain racial differences in cognitive decline.

Design, Setting, and Participants: Individual participant data from 5 cohorts (January 1971 to December 2017) were pooled from the Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represented a 0.1-SD difference in cognition. The median (interquartile range) follow-up was 12.4 (5.9-21.0) years. Analysis began September 2018.

Main Outcomes and Measures: The primary outcome was change in global cognition, and secondary outcomes were change in memory and executive function.

Exposures: Race (black vs white).

Results: Among 34 349 participants, 19 378 individuals who were free of stroke and dementia and had longitudinal BP, cognitive, and covariate data were included in the analysis. The mean (SD) age at first cognitive assessment was 59.8 (10.4) years and ranged from 5 to 95 years. Of 19 378 individuals, 10 724 (55.3%) were female and 15 526 (80.1%) were white. Compared with white individuals, black individuals had significantly faster declines in global cognition (-0.03 points per year faster [95% CI, -0.05 to -0.01]; P = .004) and memory (-0.08 points per year faster [95% CI, -0.11 to -0.06]; P < .001) but significantly slower declines in executive function (0.09 points per year slower [95% CI, 0.08-0.10]; P < .001). Time-dependent cumulative mean systolic BP level was associated with significantly faster declines in global cognition (-0.018 points per year faster per each 10-mm Hg increase [95% CI, -0.023 to -0.014]; P < .001), memory (-0.028 points per year faster per each 10-mm Hg increase [95% CI, -0.035 to -0.021]; P < .001), and executive function (-0.01 points per year faster per each 10-mm Hg increase [95% CI, -0.014 to -0.007]; P < .001). After adjusting for cumulative mean systolic BP, differences between black and white individuals in cognitive slopes were attenuated for global cognition (-0.01 points per year [95% CI, -0.03 to 0.01]; P = .56) and memory (-0.06 points per year [95% CI, -0.08 to -0.03]; P < .001) but not executive function (0.10 points per year [95% CI, 0.09-0.11]; P < .001).

Conclusions and Relevance: These results suggest that black individuals' higher cumulative BP levels may contribute to racial differences in later-life cognitive decline.

1 aLevine, Deborah, A1 aGross, Alden, L1 aBriceño, Emily, M1 aTilton, Nicholas1 aKabeto, Mohammed, U1 aHingtgen, Stephanie, M1 aGiordani, Bruno, J1 aSussman, Jeremy, B1 aHayward, Rodney, A1 aBurke, James, F1 aElkind, Mitchell, S V1 aManly, Jennifer, J1 aMoran, Andrew, E1 aKulick, Erin, R1 aGottesman, Rebecca, F1 aWalker, Keenan, A1 aYano, Yuichiro1 aGaskin, Darrell, J1 aSidney, Stephen1 aYaffe, Kristine1 aSacco, Ralph, L1 aWright, Clinton, B1 aRoger, Veronique, L1 aAllen, Norrina, Bai1 aGalecki, Andrzej, T uhttps://chs-nhlbi.org/node/839802795nas a2200313 4500008004100000022001400041245013700055210006900192260000900261300001400270490000700284520181400291100002302105700002002128700002302148700002302171700002602194700002602220700002002246700002402266700002002290700002302310700002502333700002202358700002202380700002002402700002302422856003602445 2021 eng d a1875-890800aPre-Statistical Considerations for Harmonization of Cognitive Instruments: Harmonization of ARIC, CARDIA, CHS, FHS, MESA, and NOMAS.0 aPreStatistical Considerations for Harmonization of Cognitive Ins c2021 a1803-18130 v833 a

BACKGROUND: Meta-analyses of individuals' cognitive data are increasing to investigate the biomedical, lifestyle, and sociocultural factors that influence cognitive decline and dementia risk. Pre-statistical harmonization of cognitive instruments is a critical methodological step for accurate cognitive data harmonization, yet specific approaches for this process are unclear.

OBJECTIVE: To describe pre-statistical harmonization of cognitive instruments for an individual-level meta-analysis in the blood pressure and cognition (BP COG) study.

METHODS: We identified cognitive instruments from six cohorts (the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Coronary Artery Risk Development in Young Adults study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis, and Northern Manhattan Study) and conducted an extensive review of each item's administration and scoring procedures, and score distributions.

RESULTS: We included 153 cognitive instrument items from 34 instruments across the six cohorts. Of these items, 42%were common across ≥2 cohorts. 86%of common items showed differences across cohorts. We found administration, scoring, and coding differences for seemingly equivalent items. These differences corresponded to variability across cohorts in score distributions and ranges. We performed data augmentation to adjust for differences.

CONCLUSION: Cross-cohort administration, scoring, and procedural differences for cognitive instruments are frequent and need to be assessed to address potential impact on meta-analyses and cognitive data interpretation. Detecting and accounting for these differences is critical for accurate attributions of cognitive health across cohort studies.

1 aBriceño, Emily, M1 aGross, Alden, L1 aGiordani, Bruno, J1 aManly, Jennifer, J1 aGottesman, Rebecca, F1 aElkind, Mitchell, S V1 aSidney, Stephen1 aHingtgen, Stephanie1 aSacco, Ralph, L1 aWright, Clinton, B1 aFitzpatrick, Annette1 aFohner, Alison, E1 aMosley, Thomas, H1 aYaffe, Kristine1 aLevine, Deborah, A uhttps://chs-nhlbi.org/node/891903920nas a2200505 4500008004100000022001400041245005800055210005700113260001500170300001200185490000600197520255500203653000902758653002602767653002202793653001902815653002302834653001102857653001102868653001602879653000902895653001602904653001702920653001802937100002302955700002002978700002302998700002103021700002303042700002303065700002303088700002003111700002403131700002603155700002303181700002603204700002303230700002003253700002003273700001803293700002303311700002003334700002403354856003603378 2021 eng d a2574-380500aSex Differences in Cognitive Decline Among US Adults.0 aSex Differences in Cognitive Decline Among US Adults c2021 02 01 ae2101690 v43 a

Importance: Sex differences in dementia risk are unclear, but some studies have found greater risk for women.

Objective: To determine associations between sex and cognitive decline in order to better understand sex differences in dementia risk.

Design, Setting, and Participants: This cohort study used pooled analysis of individual participant data from 5 cohort studies for years 1971 to 2017: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Linear mixed-effects models were used to estimate changes in each continuous cognitive outcome over time by sex. Data analysis was completed from March 2019 to October 2020.

Exposure: Sex.

Main Outcomes and Measures: The primary outcome was change in global cognition. Secondary outcomes were change in memory and executive function. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition.

Results: Among 34 349 participants, 26 088 who self-reported Black or White race, were free of stroke and dementia, and had covariate data at or before the first cognitive assessment were included for analysis. Median (interquartile range) follow-up was 7.9 (5.3-20.5) years. There were 11 775 (44.7%) men (median [interquartile range] age, 58 [51-66] years at first cognitive assessment; 2229 [18.9%] Black) and 14 313 women (median [interquartile range] age, 58 [51-67] years at first cognitive assessment; 3636 [25.4%] Black). Women had significantly higher baseline performance than men in global cognition (2.20 points higher; 95% CI, 2.04 to 2.35 points; P < .001), executive function (2.13 points higher; 95% CI, 1.98 to 2.29 points; P < .001), and memory (1.89 points higher; 95% CI, 1.72 to 2.06 points; P < .001). Compared with men, women had significantly faster declines in global cognition (-0.07 points/y faster; 95% CI, -0.08 to -0.05 points/y; P < .001) and executive function (-0.06 points/y faster; 95% CI, -0.07 to -0.05 points/y; P < .001). Men and women had similar declines in memory (-0.004 points/y faster; 95% CI, -0.023 to 0.014; P = .61).

Conclusions and Relevance: The results of this cohort study suggest that women may have greater cognitive reserve but faster cognitive decline than men, which could contribute to sex differences in late-life dementia.

10aAged10aCognitive Dysfunction10aCognitive Reserve10aCohort Studies10aExecutive Function10aHumans10aMemory10aMiddle Aged10aRisk10aSex Factors10aTime Factors10aUnited States1 aLevine, Deborah, A1 aGross, Alden, L1 aBriceño, Emily, M1 aTilton, Nicholas1 aGiordani, Bruno, J1 aSussman, Jeremy, B1 aHayward, Rodney, A1 aBurke, James, F1 aHingtgen, Stephanie1 aElkind, Mitchell, S V1 aManly, Jennifer, J1 aGottesman, Rebecca, F1 aGaskin, Darrell, J1 aSidney, Stephen1 aSacco, Ralph, L1 aTom, Sarah, E1 aWright, Clinton, B1 aYaffe, Kristine1 aGalecki, Andrzej, T uhttps://chs-nhlbi.org/node/870904341nas a2200385 4500008004100000022001400041245006700055210006600122260001600188520323500204100002603439700001203465700001703477700002603494700001503520700002103535700002303556700002303579700001903602700002603621700002303647700002003670700001903690700002203709700002003731700002003751700002003771700002003791700002103811700002003832700002303852700002103875700002303896856003603919 2023 eng d a2168-615700aAssociation Between Acute Myocardial Infarction and Cognition.0 aAssociation Between Acute Myocardial Infarction and Cognition c2023 May 303 a

IMPORTANCE: The magnitude of cognitive change after incident myocardial infarction (MI) is unclear.

OBJECTIVE: To assess whether incident MI is associated with changes in cognitive function after adjusting for pre-MI cognitive trajectories.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study included adults without MI, dementia, or stroke and with complete covariates from the following US population-based cohort studies conducted from 1971 to 2019: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis, and Northern Manhattan Study. Data were analyzed from July 2021 to January 2022.

EXPOSURES: Incident MI.

MAIN OUTCOMES AND MEASURES: The main outcome was change in global cognition. Secondary outcomes were changes in memory and executive function. Outcomes were standardized as mean (SD) T scores of 50 (10); a 1-point difference represented a 0.1-SD difference in cognition. Linear mixed-effects models estimated changes in cognition at the time of MI (change in the intercept) and the rate of cognitive change over the years after MI (change in the slope), controlling for pre-MI cognitive trajectories and participant factors, with interaction terms for race and sex.

RESULTS: The study included 30 465 adults (mean [SD] age, 64 [10] years; 56% female), of whom 1033 had 1 or more MI event, and 29 432 did not have an MI event. Median follow-up was 6.4 years (IQR, 4.9-19.7 years). Overall, incident MI was not associated with an acute decrease in global cognition (-0.18 points; 95% CI, -0.52 to 0.17 points), executive function (-0.17 points; 95% CI, -0.53 to 0.18 points), or memory (0.62 points; 95% CI, -0.07 to 1.31 points). However, individuals with incident MI vs those without MI demonstrated faster declines in global cognition (-0.15 points per year; 95% CI, -0.21 to -0.10 points per year), memory (-0.13 points per year; 95% CI, -0.22 to -0.04 points per year), and executive function (-0.14 points per year; 95% CI, -0.20 to -0.08 points per year) over the years after MI compared with pre-MI slopes. The interaction analysis suggested that race and sex modified the degree of change in the decline in global cognition after MI (race × post-MI slope interaction term, P = .02; sex × post-MI slope interaction term, P = .04), with a smaller change in the decline over the years after MI in Black individuals than in White individuals (difference in slope change, 0.22 points per year; 95% CI, 0.04-0.40 points per year) and in females than in males (difference in slope change, 0.12 points per year; 95% CI, 0.01-0.23 points per year).

CONCLUSIONS: This cohort study using pooled data from 6 cohort studies found that incident MI was not associated with a decrease in global cognition, memory, or executive function at the time of the event compared with no MI but was associated with faster declines in global cognition, memory, and executive function over time. These findings suggest that prevention of MI may be important for long-term brain health.

1 aJohansen, Michelle, C1 aYe, Wen1 aGross, Alden1 aGottesman, Rebecca, F1 aHan, Dehua1 aWhitney, Rachael1 aBriceño, Emily, M1 aGiordani, Bruno, J1 aShore, Supriya1 aElkind, Mitchell, S V1 aManly, Jennifer, J1 aSacco, Ralph, L1 aFohner, Alison1 aGriswold, Michael1 aPsaty, Bruce, M1 aSidney, Stephen1 aSussman, Jeremy1 aYaffe, Kristine1 aMoran, Andrew, E1 aHeckbert, Susan1 aHughes, Timothy, M1 aGalecki, Andrzej1 aLevine, Deborah, A uhttps://chs-nhlbi.org/node/9377