Sex Differences in Cognitive Decline Among US Adults | Dementia and Cognitive Impairment | JAMA Network Open | JAMA Network
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Figure 1.  Derivation of Participant Cohort
Derivation of Participant Cohort

BP indicates blood pressure.

aCategories for missing data on covariates are not mutually exclusive. Missing data for covariates included glucose (261 participants), alcohol use (18 participants), body mass index (33 participants), waist circumference (109 participants), smoking (3 participants), physical activity (30 participants), low-density lipoprotein cholesterol (264 participants), antihypertensive medication use (25 participants), and education (179 participants). No participants were missing history of atrial fibrillation.

Figure 2.  Projected Mean Changes in Global Cognition, Executive Function, and Memory Over Time by Sex
Projected Mean Changes in Global Cognition, Executive Function, and Memory Over Time by Sex

Participant-specific (conditional) projected values of cognition were calculated for a 70-year-old Black participant (woman vs man) with the following values of all covariates at or before first cognitive assessment: Northern Manhattan Study cohort, eighth grade or lower education, 0 alcoholic drinks per week, nonsmoking, body mass index of 27.1 (calculated as weight in kilograms divided by height in meters squared), waist circumference (96.0 cm), low-density lipoprotein cholesterol (123.8 mg/dL [to convert to millimoles per liter, multiply by 0.0259]) and glucose (97.3 mg/dL [to convert to millimoles per liter, multiply by 0.0555]), no history of atrial fibrillation, no hypertension treatment, and a baseline systolic blood pressure (BP) of 150 mm Hg that increases by 1 mm each year.

Random effects for this projection were set to zero. Linear mixed-effects models included time since first cognitive assessment and baseline values (measured before or at time of first cognitive assessment) of sex, age, race, cohort study, years of school, alcohol use, cigarette smoking, body mass index, waist circumference, physical activity, cumulative mean systolic BP, hypertension treatment, fasting glucose, low-density lipoprotein cholesterol, history of atrial fibrillation, age × follow-up time, sex × follow-up time, race × follow-up time, cumulative mean systolic BP × follow-up time, and hypertension treatment × follow-up time.

Table 1.  Characteristics of Participants at First Cognitive Assessment by Sex
Characteristics of Participants at First Cognitive Assessment by Sex
Table 2.  Association of Cognition Decline With Sex Adjusted for Patient Factorsa
Association of Cognition Decline With Sex Adjusted for Patient Factorsa
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    Original Investigation
    Neurology
    February 25, 2021

    Sex Differences in Cognitive Decline Among US Adults

    Author Affiliations
    • 1Cognitive Health Services Research Program, Department of Internal Medicine, University of Michigan, Ann Arbor
    • 2Department of Neurology and Stroke Program, University of Michigan, Ann Arbor
    • 3Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor
    • 4Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
    • 5Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor
    • 6Department of Psychiatry, University of Michigan, Ann Arbor
    • 7Michigan Alzheimer’s Disease Center, University of Michigan, Ann Arbor
    • 8VA Ann Arbor Healthcare System, Ann Arbor, Michigan
    • 9Vagelos College of Physicians and Surgeons, Department of Neurology, Columbia University, New York, New York
    • 10Mailman School of Public Health, Department of Epidemiology, Columbia University, New York, New York
    • 11Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, New York
    • 12Department of Neurology, Johns Hopkins University, Baltimore, Maryland
    • 13Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
    • 14Kaiser Permanente Northern California Division of Research, Oakland
    • 15Department of Neurology, University of Miami, Miami, Florida
    • 16Division of Clinical Research, National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland
    • 17Department of Psychiatry, University of California, San Francisco
    • 18Department of Neurology, University of California, San Francisco
    • 19Department of Epidemiology, University of California, San Francisco
    • 20Department of Biostatistics, University of Michigan, Ann Arbor
    JAMA Netw Open. 2021;4(2):e210169. doi:10.1001/jamanetworkopen.2021.0169
    Key Points

    Question  Does the risk of cognitive decline among US adults vary by sex?

    Findings  In this cohort study using pooled data from 26 088 participants, women, compared with men, had higher baseline performance in global cognition, executive function, and memory. Women, compared with men, had significantly faster declines in global cognition and executive function, but not memory.

    Meaning  These findings suggest that women may have greater cognitive reserve but faster cognitive decline than men.

    Abstract

    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.

    Introduction

    Sex differences in dementia risk are unclear. It is known that women have a greater prevalence of Alzheimer disease (AD) than men, at least partly because women live longer.1-3 Some, but not all, studies suggest that women have higher incidence of AD.4-6 Sex differences in biological factors (eg, sex hormones), health factors (eg, cardiovascular risk), and social factors (eg, education levels) are hypothesized to contribute to sex differences in dementia risk.7,8 However, most studies have focused on the effects of cardiovascular risk and education on sex disparities in late-life dementia.9,10 Whether cognitive trajectories differ by sex after accounting for sex differences in cardiovascular risk and education levels is unknown. Using a pooled cohort11 of 5 diverse, well-characterized, population-based cohort studies with repeated objective measures of cognition, we conducted a study to assess sex differences in later-life cognitive trajectories. We hypothesized that women have greater cognitive decline than men after adjusting for potential confounders.

    Methods
    Study Design, Participants, and Measurements

    The report follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies. This pooled analysis examined individual participant data from 5 well-characterized prospective cohort studies in the US with repeated measures of cognition: Atherosclerosis Risk in Communities Study (ARIC),12 Coronary Artery Risk Development in Young Adults Study (CARDIA),13 Cardiovascular Health Study (CHS),14 Framingham Offspring Study (FOS),15 and Northern Manhattan Study (NOMAS)16 for years 1971 to 2017 (eAppendix in the Supplement).

    Inclusion criteria included no history of dementia or stroke at each cohort’s baseline (because stroke can alter cognitive trajectory)17 and no incidence of dementia or stroke before first cognitive assessment. We excluded participants who reported race other than Black or White because so few participants of other races were reported throughout the study cohorts as to preclude examining the association between other race and the dependent variable. We excluded participants reporting Hispanic ethnicity from NOMAS because other cohorts did not collect information on Hispanic ethnicity or had few participants reporting Hispanic ethnicity; therefore it would be difficult to separate the effect of the NOMAS cohort from the effect of Hispanic ethnicity. We required participants to have 1 or more assessments of cognition and 1 or more measurements of blood pressure (BP) at or before the first measurement of cognition because BP is a risk factor for cognitive decline11,18 and varies by sex.18,19 The University of Michigan institutional review board approved this study. Participating institutions approved the cohort studies, and participants provided written informed consent.

    Cognitive Function Assessments

    Trained cohort staff administered in-person cognitive function tests longitudinally; cognitive tests have been validated in Black and White participants20,21 and are consistent with the Vascular Cognitive Impairment Harmonization Standards.22 In 3 cohorts (ARIC, NOMAS, and CHS), trained staff also administered tests of global cognitive function (but not tests of memory or executive function) by telephone for participants unable to attend some exam visits. Cognitive tests of global cognition can be measured reliably and precisely over the telephone in adults with comparable results.23

    In order to resolve the challenge of different cognitive tests administered across the cohorts, we cocalibrated available cognitive test items into factors representing global cognition (ie, global cognitive performance), memory (learning and delayed recall/recognition), and executive function (complex and/or speeded cognitive functions) using item response theory methods (eg, a graded response model) that can accommodate both cognitive information in common across cohorts and test items unique to particular cohorts.23,24 Cognitive factor score outcomes, estimated using the regression-based method in Mplus,25,26 were set to a t score metric (mean [SD] score, 50 [10]) at a participant’s first cognitive assessment; a 1-point difference represents a 0.1-SD difference in the distribution of cognition across the 5 cohorts. Higher cognitive scores indicate better performance (eAppendix in the Supplement). The primary outcome was change in global cognition. Secondary outcomes were change in memory and executive function.

    Covariates

    We used covariates measured closest to, but not after, the first cognitive assessment. Demographic characteristics considered included sex, age, race, years of school, and cohort study. Participants self-reported sex and race. Vascular risk factors included alcohol use, cigarette smoking, body mass index (calculated as weight in kilograms divided by height in meters squared), waist circumference, physical activity, fasting glucose, low-density lipoprotein cholesterol, history of atrial fibrillation, and systolic BP. We used systolic BP, summarized as the time-dependent cumulative mean of all BPs before each cognitive measurement, because systolic BP tends to have a stronger association with BP-related outcomes than diastolic BP.18,27,28 Long-term cumulative mean systolic BP has improved prediction of clinical outcomes compared with single BP measurements29 or mean BP over discrete intervals (eg, ≤1 year, 1 to 5 years) before outcome measurement,28 and time-dependent cumulative mean systolic BP is associated with cognitive trajectories.11 Cohorts measured current hypertension medication use by evidence of medication bottles and self-report (eAppendix in the Supplement).

    Statistical Analysis

    Following a prespecified analysis plan, we compared participant characteristics by sex using a Wilcoxon rank sum test or χ2 test as appropriate. We used linear mixed-effects models to estimate changes in each continuous cognitive outcome over time by sex. Because the pooled data involved a small number of cohorts (ie, 5 studies), we associated a fixed effect with cohorts when pooling the data. To estimate sex differences in cognitive changes, models included sex and a sex × follow-up time interaction term. The models included covariates listed in Table 1, and 2-way interaction terms involving follow-up time crossed with age at the time of first cognitive assessment, race, time-dependent cumulative mean systolic BP, and hypertension treatment at the time of first cognitive assessment, and subject-specific random effects for intercepts and slopes. Follow-up time was treated as a continuous measure defined as years since first measurement of each cognitive outcome.

    For each outcome, all available cognitive observations were used in the primary analysis except observations after the time of first cohort-adjudicated incident stroke during follow-up, because incident stroke alters the cognitive trajectory.17 We evaluated model assumptions by inspecting residual plots. There was no evidence of nonlinear effects of covariates and a significant race × sex × time interaction on cognitive trajectories.

    We performed a complete case analysis, excluding a small number of participants (693 of 26 781 [2.59%]) from the analytical data set that had missing values in covariates. Statistical significance for all analyses was set as P < .05 in 2-sided tests. All analyses were performed using SAS version 9.4 (SAS Institute).

    Sensitivity Analysis

    We repeated analyses (1) including participants’ cognitive observations after the time of incident stroke, (2) after adding kidney function (glomerular filtration rate30) and history of myocardial infarction because they may be on the causal pathway, (3) adding the number of APOE ε4 alleles and an APOE ε4 × follow-up time interaction term, and (4) within cohorts to assess heterogeneity in the associations between sex and cognitive decline.

    Results

    The study sample included 26 088 participants, 11 775 men (45.1%) (median [interquartile range {IQR}] age, 58 [51-66] years at first cognitive assessment; 2229 [18.9%] Black) and 14 313 women (54.9%) (median [IQR] age, 58 [51-67] years at first cognitive assessment; 3636 [25.4%] Black). Figure 1 shows the derivation of the cohort from the pooled sample. Table 1 presents demographic and clinical characteristics of participants by sex. Most participants completed 2 or more cognitive assessments (22 364 participants [85.7%]). During a median (IQR) follow-up of 7.9 (5.3-20.5) years, the median (IQR) number of global cognition assessments was 3 (2-5) for women and men, the median (IQR) number of executive function assessments was 2 (2-4) for women and men, and the median (IQR) number of memory assessments was 2 (1-3) for women and 2 (2-3) for men. eTable 1 in the Supplement shows characteristics of study participants by cohort. Because the secondary outcome measures were performed less frequently, the executive function analysis included 24 392 participants and the memory analysis included 20 191 participants. eTable 2 in the Supplement has information on missing data and attrition.

    Change in Global Cognition

    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) (Table 2). Women, compared with men, had significantly faster declines in global cognition (Figure 2 and Table 2). White men at a median age of 58 years experienced mean declines in global cognition of 0.21 points per year (95% CI, −0.22 to −0.20 point/y; P < .001). White women of similar age experienced mean declines in global cognition of 0.27 points per year (95% CI, −0.29 to −0.26 points/y). The adjusted difference in slope was −0.07 points per year faster in women (95% CI, −0.08 to −0.05 points/y; P < .001).

    Changes in Executive Function and Memory

    Women had significantly higher baseline performance than men in 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) (Table 2). Compared with men, women had significantly faster declines in executive function (−0.06 points/y faster; 95% CI, −0.07 to −0.05 points; P < .001) but not in memory (−0.004 points/y faster; 95% CI, −0.023 to 0.014 points; P = .61) (Figure 2 and Table 2).

    Sensitivity Analysis

    Results were similar in analyses including participants’ cognitive observations after the time of incident stroke, adding glomerular filtration rate and history of myocardial infarction as covariates, and adding APOE ε4 and APOE ε4 × time variables as covariates (eTables 3-5 in the Supplement). There was little heterogeneity in the associations between sex and cognitive decline across cohorts (eTable 6 in the Supplement).

    Discussion

    Among 26 088 individuals pooled from 5 prospective cohort studies, women had higher baseline performance than men in global cognition, executive function, and memory. Women, compared with men, had significantly faster declines in global cognition and executive function but not memory. These sex differences persisted after accounting for the influence of age, race, education, and cumulative mean BP.

    Our results provide evidence suggesting that women have greater cognitive reserve but faster cognitive decline than men, independent of sex differences in cardiovascular risk factors and educational years. Previous studies31 have shown that women have higher initial scores on most types of cognitive tests except those measuring visuospatial ability. Few studies have examined sex differences in cognitive trajectories in population-based cohorts of cognitively normal Black and White individuals. A 2016 study31 of older adults in Baltimore (mean ages 64-70 years) found that men had steeper rates of decline on 4 of 12 cognitive tests (mental status [Mini Mental State Examination], perceptuomotor speed and integration, visual memory, and visuospatial ability) but no sex differences in declines on 8 of 12 cognitive tests (verbal learning and memory, object recognition and semantic retrieval, fluent language production, attention, working memory and set-shifting, perceptuomotor speed, and executive function). Similarly, we found no sex differences in verbal learning and memory; but, in contrast, we found that women had faster cognitive decline in global cognitive performance and executive function than men. These latter results might differ because we included young and middle-aged adults (mean age 58 years). Our findings are consistent with studies showing that women with mild cognitive impairment or AD have faster decline in global cognition than men.32,33

    Our results of sex differences in cognitive decline were consistent across most cohorts. The potential reasons for the finding of slower cognitive decline in women in the Framingham Offspring Study are unclear and might be due to socioeconomic, life stress, geographic, and environmental factors as well as cohort differences in sampling strategies, eligibility criteria, and cognitive tests. Although our finding that declines in memory do not differ by sex are consistent with other studies,31 the finding is surprising because memory decline is the clinical hallmark of AD, a common cause of dementia,1 and some studies suggest that women have higher incidence of AD.4-6 One explanation is that women manifest verbal memory declines at more advanced stages of neurodegenerative disease than men owing to women having greater initial verbal memory scores and cognitive reserve.34,35 However, evidence against this explanation is that women in our study had faster declines in global cognition and executive function despite having higher initial levels of these measures. Another explanation is that the memory measure was less sensitive than the global cognition and executive function measures to detect sex differences in cognitive decline.

    If the observed sex differences in declines in global cognition and executive function are causal, then they would be clinically significant, equivalent to 5 to 6 years of cognitive aging. The faster declines in mean cognitive scores associated with female sex can be related to approximate equivalent changes in years of brain or cognitive aging by calculating the ratio of slope coefficients for female sex and baseline age on cognition. Experts have defined clinically meaningful cognitive decline as a decline in cognitive function of 0.5 or more SDs from baseline cognitive scores.36-38 Women will reach the threshold of a 0.5-SD decrease from the baseline score 4.72 years faster than men for global cognition, 1.97 years faster for executive function, and 0.24 years faster for memory (eTable 7 in the Supplement). Based on this approach, sex differences in cognitive declines are clinically meaningful. Declines in global cognition and executive function markedly raise the risk of death, dementia, and functional disability.39-41 Diagnosis of the clinical syndrome of dementia/neurocognitive disorder requires cognitive decline by history and objective measurement.42 Our findings that women have faster declines in global cognition and executive function mean women would have greater risk than men for being diagnosed with dementia based on objectively measured cognitive decline. Our findings that women had higher initial cognitive scores suggest informants and clinicians might not observe significant cognitive decline in women until substantial loss and impairment has occurred.

    Studies have consistently found evidence of sex differences in baseline cognitive functioning with women demonstrating stronger verbal cognitive skills than men, but men demonstrating stronger visuospatial skills than women (eg, mental rotations).31,43 Reasons for these sex differences are complex and likely influenced by biological (eg, sex hormones), genetic (eg, APOE), and social and cultural factors.43 While sex differences in cognitive reserve might also be associated with differences in life course risk factors such as vascular risk,44 education, and health behaviors such as smoking and exercise,45 our findings of sex differences in baseline cognitive performance independent of these factors suggest that additional contributors and biological pathways play a role.

    Women might have faster cognitive decline than men because of differences in sex hormones, structural brain development, genetics, psychosocial factors, lifestyle factors, functional connectivity, and tau pathology.45-47 Women might have greater burden of small vessel disease, including white matter hyperintensity volume, and less axonal structural integrity that in turn leads to faster cognitive decline particularly in executive function and processing speed.48,49 Women also appear to have lower gray matter volume,50 so they might be more vulnerable to both the accelerated gray volume loss that occurs with aging and the differential volume loss in specific brain regions that occurs with neurodegenerative diseases.51 Recent studies suggest that women develop greater neurofibrillary degeneration, brain parenchymal loss, and cognitive decline.52-54 Our results suggest that women’s greater cognitive reserve might enable them to withstand greater AD-pathology than men.

    Strengths and Limitations

    Our study has several strengths. By pooling 5 large, high-quality cohorts, we had longitudinal cognitive assessments and vascular risk factor measurements in a large number of Black and White individuals who were young, middle-aged, and older-aged to estimate cognitive trajectories in men and women. We had repeated cognitive measures during up to 21 years of follow-up. The cohort studies included in our study systematically measured major cognitive domains important for daily, occupational, and social functioning: global cognition, executive function, and memory. Our findings were consistent across cohorts.

    This study also has several limitations. While we adjusted for educational years, we could not adjust for educational quality, literacy, other socioeconomic factors,10 or depressive symptoms, because not all cohorts had these data at or before the first cognitive assessment. However, studies suggest that socioeconomic factors tend to influence initial cognitive scores (ie, intercepts) rather than the change in cognitive scores over time (slopes).55,56 Selective attrition of cognitively impaired participants could underestimate the rate of cognitive decline57 or not.58 Estimating the potential clinical impact of sex differences in cognitive decline by correlating it with decline due to aging is a common approach, but it does not directly measure clinical impact, and a clinically meaningful change might vary by an individual’s age, educational quality, race, and baseline cognition.59 There were no sex differences in participants excluded because of stroke or dementia before first cognitive assessment, so this would not influence sex differences in cognitive decline (eTable 8 in the Supplement).

    We did not study incident dementia because some cohort studies lacked this information. By design, we did not adjust for baseline cognition. We also did not study any particular age interval associated with greatest risk of sex-related cognitive decline. Heterogeneity of the association of sex with cognitive decline between cohorts might have affected the statistical validity of the summary estimate of the effect in the pooled cohort. Smaller sample size and fewer cognitive assessments might have reduced precision of estimates of cognitive decline in executive function and memory (ie, the secondary outcomes). We did not have information on participants’ instrumental activities of daily living, family history of dementia, and hormone replacement therapy use. While the assumption that participants’ postmortem cognitive data are missing at random might lead to immortal cohort bias and underestimate memory declines,60 it is valid to answer the research question quantifying sex differences in cognitive trajectories through study follow-up. Women might have had a greater likelihood of regressing to a lower value than men at follow-up because they had higher baseline cognitive function than men. Using a fixed effect for cohorts might have produced conservative estimates of sex effects on cognitive slopes.

    Conclusions

    These results suggest that women have greater cognitive reserve but faster later-life cognitive decline than men. Evidence suggests that dementia incidence in Europe and the US has declined over the past 25 years, but declines were less in women than in men.61 Our findings suggest that women are at risk for delayed identification of cognitive decline, yet more rapid trajectory of decline, suggesting increased risk of dementia and disability compared with men, consistent with research showing that women with mild cognitive impairment or AD have faster cognitive decline than men.32,33 Women may thus have greater needs for caregiving and functional support resources, particularly given women’s longer life expectancy compared with men. Women may also have greater need for serial cognitive assessment to allow for earlier detection of cognitive decline.

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    Article Information

    Accepted for Publication: January 6, 2021.

    Published: February 25, 2021. doi:10.1001/jamanetworkopen.2021.0169

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Levine DA et al. JAMA Network Open.

    Corresponding Author: Deborah A. Levine, MD, MPH, Division of General Medicine, University of Michigan, 2800 Plymouth Rd, NCRC 16-430W, Ann Arbor, MI 48109-2800 (deblevin@umich.edu).

    Author Contributions: Drs Galecki and Tilton had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Levine, Tilton, Hayward, Burke, Elkind, Tom, Galecki.

    Acquisition, analysis, or interpretation of data: Levine, Gross, Briceño, Tilton, Giordani, Sussman, Hayward, Hingtgen, Elkind, Manly, Gottesman, Gaskin, Sidney, Sacco, Wright, Yaffe, Galecki.

    Drafting of the manuscript: Levine, Briceño, Hingtgen, Galecki.

    Critical revision of the manuscript for important intellectual content: Gross, Briceño, Tilton, Giordani, Sussman, Hayward, Burke, Elkind, Manly, Gottesman, Gaskin, Sidney, Sacco, Tom, Wright, Yaffe.

    Statistical analysis: Gross, Tilton, Sussman, Hayward, Galecki.

    Obtained funding: Levine, Elkind, Sidney, Sacco, Galecki.

    Administrative, technical, or material support: Levine, Briceño, Sussman, Hingtgen, Wright.

    Supervision: Levine, Sacco, Galecki.

    Conflict of Interest Disclosures: Dr Levine reported receiving consulting fees and grants from the National Institutes of Health (NIH)/ National Institute on Aging (NIA) outside the submitted work. Dr Tilton reported receiving consulting fees and grants from NIH/NIA outside the submitted work. Dr Hayward reported receiving grants from the US Veterans Affairs Department during the conduct of the study. Dr Burke reported grants from the NIH outside the submitted work. Dr Gottesman reported receiving grants from American Academy of Neurology and previous editorial work at the journal Neurology outside the submitted work. Dr Gaskin reported receiving grants from the US Centers for Disease Control and Prevention during the conduct of the study and personal fees from Altarum and the Robert Wood Johnson Foundation outside the submitted work. Dr Sidney reported receiving grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Sacco reported receiving grants from the NIH Northern Manhattan Study during the conduct of the study and grants from Florida Department of Health Florida Stroke Registry, grants from the NIH Miami Clinical Translational Science Institute, and compensation as editor-in-chief of the American Heart Association’s Stroke outside the submitted work. Dr Wright reported receiving grants from the NIH during the conduct of the study and royalty fees from UpToDate.com outside the submitted work. No other disclosures were reported.

    Funding/Support: This study was supported by grant R01 NS102715 from the National Institute of Neurological Disorders and Stroke (NINDS), NIH, US Department of Health and Human Service. Additional funding was provided by the National Institute of Aging (NIA) grant R01 AG051827 (Dr Levine), NIA Claude Pepper Center grant P30 AG024824 (Dr Galecki), NIA grants K01 AG050699 (Dr Gross) and K01 AG050723 (Dr Tom), and NIA Michigan Alzheimer’s Disease Research Center grant P30 AG053760 (Dr Giordani).

    Role of the Funder/Sponsor: The NINDS was not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation or approval of the manuscript; and decision to submit the manuscript for publication. One representative (Dr Wright) of the funding agency reviewed the manuscript.

    Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of NINDS or the NIH.

    Additional Contributions: The authors thank the staff and participants of the ARIC study for their important contributions.

    Additional Information: Cohort Funding/Support: The Atherosclerosis Risk in Communities (ARIC) study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, US Department of Health and Human Services (under contracts HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I). The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the NHLBI in collaboration with the University of Alabama at Birmingham (HHSN268201800005I and HHSN268201800007I), Northwestern University (HHSN268201800003I), University of Minnesota (HHSN268201800006I), and Kaiser Foundation Research Institute (HHSN268201800004I). This manuscript has been reviewed by CARDIA for scientific content. The Cardiovascular Health Study (CHS) was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, 379 N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, 380 N01HC85086, and grants U01HL080295 and U01HL130114 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by grants (Nos. R01AG023629, R01AG15928, and R01AG20098) from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The Framingham Heart Study is a project of the NHLBI of the National Institutes of Health and Boston University School of Medicine. This project has been funded in whole or in part with Federal funds from the NHLBI, under contract No. HHSN268201500001I. The Northern Manhattan Stroke study has been funded at least in part with federal funds from the National Institutes of Health, National Institute of Neurological Disorders and Stroke by grant No. R01 NS29993.

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