Overcoming Data Gaps in Life Course Epidemiology by Matching Across Cohorts.

Life course epidemiology is hampered by the absence of large studies with exposures and outcomes measured at different life stages in the same individuals. We describe when the effect of an exposure ( A ) on an outcome ( Y ) in a target population is identifiable in a combined ("synthetic") cohort created by pooling an early-life cohort including measures of A with a late-life cohort including measures of Y . We enumerate causal assumptions needed for unbiased effect estimation in the synthetic cohort and illustrate by simulating target populations under four causal models. From each target population, we randomly sampled early- and late-life cohorts and created a synthetic cohort by matching individuals from the two cohorts based on mediators and confounders. We estimated the effect of A on Y in the synthetic cohort, varying matching variables, the match ratio, and the strength of association between matching variables and A . Finally, we compared bias in the synthetic cohort estimates when matching variables did not d-separate A and Y to the bias expected in the original cohort. When the set of matching variables includes all variables d-connecting exposure and outcome (i.e., variables blocking all backdoor and front-door pathways), the synthetic cohort yields unbiased effect estimates. Even when matching variables did not fully account for confounders, the synthetic cohort estimate was sometimes less biased than comparable estimates in the original cohort. Methods based on merging cohorts may hasten the evaluation of early- and mid-life determinants of late-life health but rely on available measures of both confounders and mediators.

Genetic risk score for Alzheimer's disease predicts brain volume differences in mid and late life in UK biobank participants.

INTRODUCTION: We estimated the ages when associations between Alzheimer's disease (AD) genes and brain volumes begin among middle-aged and older adults. METHODS: Among 45,616 dementia-free participants aged 45-80, linear regressions tested whether genetic risk score for AD (AD-GRS) had age-dependent associations with 38 regional brain magnetic resonance imaging volumes. Models were adjusted for sex, assessment center, genetic ancestry, and intracranial volume. RESULTS: AD-GRS modified the estimated effect of age (per decade) on the amygdala (-0.41 mm3 [-0.42, -0.40]); hippocampus (-0.45 mm3 [-0.45, -0.44]), nucleus accumbens (-0.55 mm3 [-0.56, -0.54]), thalamus (-0.38 mm3 [-0.39, -0.37]), and medial orbitofrontal cortex (-0.23 mm3 [-0.24, -0.22]). Trends began by age 45 for the nucleus accumbens and thalamus, 48 for the hippocampus, 51 for the amygdala, and 53 for the medial orbitofrontal cortex. An AD-GRS excluding apolipoprotein E (APOE) was additionally associated with entorhinal and middle temporal cortices. DISCUSSION: APOE and other genes that increase AD risk predict lower hippocampal and other brain volumes by middle age.

Promoting diverse perspectives: Addressing health disparities related to Alzheimer's and all dementias.

Dementia research lacks appropriate representation of diverse groups who often face substantial adversity and greater risk of dementia. Current research participants are primarily well-resourced, non-Hispanic White, cisgender adults who live close to academic medical centers where much of the research is based. Consequently, the field faces a knowledge gap about Alzheimer's-related risk factors in those other groups. The Alzheimer's Association hosted a virtual conference on June 14-16, 2021, supported in part by the National Institute on Aging (R13 AG072859-01), focused on health disparities. The conference was held entirely online and consisted of 2 days of core programming and a day of focused meetings centered on American Indian and Alaska Natives and on LGBTQIA+ populations. Over 1300 registrants attended discussions focused on the structural and systemic inequities experienced across diverse groups, as well as ways to investigate and address these inequities.

Practical Guide to Honest Causal Forests for Identifying Heterogeneous Treatment Effects.

"Heterogeneous treatment effects" is a term which refers to conditional average treatment effects (i.e., CATEs) that vary across population subgroups. Epidemiologists are often interested in estimating such effects because they can help detect populations that may particularly benefit from or be harmed by a treatment. However, standard regression approaches for estimating heterogeneous effects are limited by preexisting hypotheses, test a single effect modifier at a time, and are subject to the multiple-comparisons problem. In this article, we aim to offer a practical guide to honest causal forests, an ensemble tree-based learning method which can discover as well as estimate heterogeneous treatment effects using a data-driven approach. We discuss the fundamentals of tree-based methods, describe how honest causal forests can identify and estimate heterogeneous effects, and demonstrate an implementation of this method using simulated data. Our implementation highlights the steps required to simulate data sets, build honest causal forests, and assess model performance across a variety of simulation scenarios. Overall, this paper is intended for epidemiologists and other population health researchers who lack an extensive background in machine learning yet are interested in utilizing an emerging method for identifying and estimating heterogeneous treatment effects.

Propensity Scores in Health Disparities Research: The Example of Cognitive Aging and the Hispanic Paradox.

BACKGROUND: Individuals of Mexican ancestry in the United States experience substantial socioeconomic disadvantages compared with non-Hispanic white individuals; however, some studies show these groups have similar dementia risk. Evaluating whether migration selection factors (e.g., education) associated with risk of Alzheimer disease and related dementia (ADRD) explain this paradoxical finding presents statistical challenges. Intercorrelation of risk factors, common with social determinants, could make certain covariate patterns very likely or unlikely to occur for particular groups, which complicates their comparison. Propensity score (PS) methods could be leveraged here to diagnose nonoverlap and help balance exposure groups. METHODS: We compare conventional and PS-based methods to examine differences in cognitive trajectories between foreign-born Mexican American, US-born Mexican American, and US-born non-Hispanic white individuals in the Health and Retirement Study (1994-2018). We examined cognition using a global measure. We estimated trajectories of cognitive decline from linear mixed models adjusted for migration selection factors also associated with ADRD risk conventionally or with inverse probability weighting. We also employed PS trimming and match weighting. RESULTS: In the full sample, where PS overlap was poor, unadjusted analyses showed both Mexican ancestry groups had worse baseline cognitive scores but similar or slower rates of decline compared with non-Hispanic white adults; adjusted findings were similar, regardless of method. Focusing analyses on populations where PS overlap was improved (PS trimming and match weighting) did not alter conclusions. CONCLUSIONS: Attempting to equalize groups on migration selection and ADRD risk factors did not explain paradoxical findings for Mexican ancestry groups in our study.

Regression discontinuity design to evaluate the effect of statins on myocardial infarction in electronic health records.

Regression discontinuity design (RDD) is a quasi-experimental method intended for causal inference in observational settings. While RDD is gaining popularity in clinical studies, there are limited real-world studies examining the performance on estimating known trial casual effects. The goal of this paper is to estimate the effect of statins on myocardial infarction (MI) using RDD and compare with propensity score matching and Cox regression. For the RDD, we leveraged a 2008 UK guideline that recommends statins if a patient's 10-year cardiovascular disease (CVD) risk score > 20%. We used UK electronic health record data from the Health Improvement Network on 49,242 patients aged 65 + in 2008-2011 (baseline) without a history of CVD and no statin use in the two years prior to the CVD risk score assessment. Both the regression discontinuity (n = 19,432) and the propensity score matched populations (n = 24,814) demonstrated good balance of confounders. Using RDD, the adjusted point estimate for statins on MI was in the protective direction and similar to the statin effect observed in clinical trials, although the confidence interval included the null (HR = 0.8, 95% CI 0.4, 1.4). Conversely, the adjusted estimates using propensity score matching and Cox regression remained in the harmful direction: HR = 2.42 (95% CI 1.96, 2.99) and 2.51 (2.12, 2.97). RDD appeared superior to other methods in replicating the known protective effect of statins with MI, although precision was poor. Our findings suggest that, when used appropriately, RDD can expand the scope of clinical investigations aimed at causal inference by leveraging treatment rules from everyday clinical practice.

Racial Residential Segregation in Young Adulthood and Brain Integrity in Middle Age: Can We Learn From Small Samples?

Racial residential segregation is associated with multiple adverse health outcomes in Black individuals. Yet, the influence of structural racism and racial residential segregation on brain aging is less understood. In this study, we investigated the association between cumulative exposure to racial residential segregation over 25 years (1985-2010) in young adulthood, as measured by the Getis-Ord Gi* statistic, and year 25 measures of brain volume (cerebral, gray matter, white matter, and hippocampal volumes) in midlife. We studied 290 Black participants with available brain imaging data who were enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a prospective cohort study. CARDIA investigators originally recruited 2,637 Black participants aged 18-30 years from 4 field centers across the United States. We conducted analyses using marginal structural models, incorporating inverse probability of treatment weighting and inverse probability of censoring weighting. We found that compared with low/medium segregation, greater cumulative exposure to a high level of racial residential segregation throughout young adulthood was associated with smaller brain volumes in general (e.g., for cerebral volume, ß = -0.08, 95% confidence interval: -0.15, -0.02) and with a more pronounced reduction in hippocampal volume, though results were not statistically significant. Our findings suggest that exposure to segregated neighborhoods may be associated with worse brain aging.

Quantifying Lifecourse Drivers of International Migration: A Cross-national Analysis of Mexico and the United States.

BACKGROUND: Evaluating the long-term health consequences of migration requires longitudinal data on migrants and non-migrants to facilitate adjustment for time-varying confounder-mediators of the effect of migration on health. METHODS: We merged harmonized data on subjects aged 50+ from the US-based Health and Retirement Study (HRS) and the Mexican Health and Aging Study (MHAS). Our exposed group includes MHAS-return migrants (n = 1555) and HRS Mexican-born migrants (n = 924). Our unexposed group includes MHAS-never migrants (n = 16,954). We constructed a lifecourse data set from birth (age 0) until either age at migration to the United States or age at study entry. To account for confounding via inverse probability of treatment weights (IPTW), we modeled the probability of migration at each year of life using time-varying pre-migration characteristics. We then evaluated the effect of migration on mortality hazard estimated with and without IPTW. RESULTS: Mexico to the United States migration was predicted by time-varying factors that occurred before migration. Using measured covariates at time of enrollment to account for selective migration, we estimated that, for women, migrating reduces mortality risk by 13%, although this estimate was imprecise and results were compatible with either large protective or deleterious associations (hazard ratio [HR] =0.87, 95% confidence interval [CI]: 0.60, 1.27). When instead using IPTWs, the estimated effect on mortality was similarly imprecise (HR = 0.98, 95% CI: 0.77, 1.25). The relationship among men was similarly uncertain in both models. CONCLUSIONS: Although time-varying social factors predicted migration, IPTW weighting did not affect our estimates. Larger samples are needed to precisely estimate the health effects of migration.

Body mass index in early adulthood and dementia in late life: Findings from a pooled cohort.

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.

Associations of Income Volatility With Incident Cardiovascular Disease and All-Cause Mortality in a US Cohort.

BACKGROUND: Income volatility is on the rise and presents a growing public health problem. Because in many epidemiological studies income is measured at a single point in time, the association of long-term income volatility with incident cardiovascular disease (CVD) and mortality has not been adequately explored. The goal of this study was to examine associations of income volatility from 1990 to 2005 with incident CVD and all-cause mortality in the subsequent 10 years. METHODS: The Coronary Artery Risk Development in Young Adults Study is an ongoing prospective cohort study conducted within urban field centers in Birmingham, AL; Chicago, IL; Minneapolis, MN; and Oakland, CA. We studied 3937 black and white participants 23 to 35 years of age in 1990 (our study baseline). Income volatility was defined as the intraindividual SD of the percent change in income across 5 assessments from 1990 to 2005. An income drop was defined as a decrease of ≥25% from the previous visit and less than the participant's average income from 1990 to 2005. CVD events (fatal and nonfatal) and all-cause mortality between 2005 and 2015 were adjudicated with the use of medical records and death certificates. CVD included primarily acute events related to heart disease and stroke. RESULTS: A total of 106 CVD events and 164 deaths occurred between 2005 and 2015 (incident rate, 2.76 and 3.66 per 1000 person-years, respectively). From Cox models adjusted for sociodemographic, behavioral, and CVD risk factors, higher income volatility and more income drops were associated with greater CVD risk (high versus low volatility: hazard ratio, 2.07; 95% CI, 1.10-3.90; ≥2 versus 0 income drops: hazard ratio, 2.54; 95% CI, 1.24-5.19) and all-cause mortality (high versus low volatility: hazard ratio, 1.78; 95% CI,1.03-3.09; ≥2 versus 0 income drops: hazard ratio, 1.92; 95% CI, 1.07-3.44). CONCLUSIONS: In a cohort of relatively young adults, income volatility and drops during a 15-year period of formative earning years were independently associated with a nearly 2-fold risk of CVD and all-cause mortality.

Results of the CARDIA study suggest that higher dietary potassium may be kidney protective.

The association between dietary sodium and potassium intake with the development of kidney disease remains unclear, particularly among younger individuals. Here, we determined whether dietary sodium and potassium intake are associated with incident chronic kidney disease (CKD) using data from 1,030 adults (age 23-35 in 1990-1991) from the Coronary Artery Risk Development In Young Adults study, based on repeated measurements of estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (ACR) from 1995 through 2015. Urinary sodium and potassium excretion (mg/day), calculated from three 24-hour urine collections in 1990-1991, were averaged to measure sodium and potassium intake. Serum creatinine was used to calculate eGFR using the CKD EPI equation; spot urine albumin and creatinine were used to calculate ACR, each at five visits from 1995-1996 through 2015-2016. CKD was defined as decreased eGFR (under 60 ml/min/1.73m2) or the development of albuminuria (ACR over 30 mg/g). We used log binomial regression models adjusted for socio-demographic, behavioral, and clinical factors to determine whether sodium and potassium intake were associated with incident CKD (decreased eGFR or developed albuminuria) among those free of CKD in 1995. Dietary sodium intake was not significantly associated with incident CKD. However, every 1,000 mg/day increment of potassium intake in 1990 was significantly associated with a 29% lower risk of incident albuminuria (relative risk 0.71, 95% confidence interval 0.53, 0.95), but not eGFR. Thus, higher dietary potassium intake may protect against the development of kidney damage, particularly albuminuria.

Association of traumatic brain injury with dementia and memory decline in older adults in the United States.

INTRODUCTION: To examine associations of history of traumatic brain injuries (TBIs) with loss of consciousness (LOC) with dementia incidence and memory decline. METHODS: We studied 2718 participants from the 1992 enrollment cohort of the Health and Retirement Study (HRS) aged 65 years or older in 2000. History of TBI with LOC was self-reported in 1992. Dementia was assessed using four algorithms established in HRS. Participants were followed from 2000 to 2014 with repeated measures of dementia and memory performance. Cox models and linear mixed-effects models were used. RESULTS: In 1992, 11.9% of the participants reported a history of TBI with LOC. In fully adjusted models for all four algorithms, participants with a history of TBI with LOC had no statistically significant difference in dementia incidence nor in memory decline, compared to participants without TBI history. DISCUSSION: Our study did not find evidence of a long-term association between history of TBI with LOC (of unknown frequency and severity) and dementia incidence or memory decline.

Sociodemographic Disparities in Long-Term Mortality Among Stroke Survivors in the United States.

Background and Purpose- It is unclear whether disparities in mortality among stroke survivors exist long term. Therefore, the purpose of the current study is to describe rates of longer term mortality among stroke survivors (ie, beyond 30 days) and to determine whether socioeconomic disparities exist. Methods- This analysis included 1329 black and white participants, aged ≥45 years, enrolled between 2003 and 2007 in the REGARDS study (Reasons for Geographic and Racial Differences in Stroke) who suffered a first stroke and survived at least 30 days after the event. Long-term mortality among stroke survivors was defined in person-years as time from 30 days after a first stroke to date of death or censoring. Mortality rate ratios (MRRs) were used to compare rates of poststroke mortality by demographic and socioeconomic characteristics. Results- Among adults who survived ≥30 days poststroke, the age-adjusted rate of mortality was 82.3 per 1000 person-years (95% CI, 75.4-89.2). Long-term mortality among stroke survivors was higher in older individuals (MRR for 75+ versus <65, 3.2; 95% CI, 2.6-4.1) and among men than women (MRR, 1.3; 95% CI, 1.1-1.6). It was also higher among those with less educational attainment (MRR for less than high-school versus college graduate, 1.5; 95% CI, 1.1-1.9), lower income (MRR for <$20k versus >50k, 1.4; 95% CI, 1.1-1.9), and lower neighborhood socioeconomic status (SES; MRR for low versus high neighborhood SES, 1.4; 95% CI, 1.1-1.7). There were no differences in age-adjusted rates of long-term poststroke mortality by race, rurality, or US region. Conclusions- Rates of long-term mortality among stroke survivors were higher among individuals with lower SES and among those residing in neighborhoods of lower SES. These results emphasize the need for improvements in long-term care poststroke, especially among individuals of lower SES.

Progress and future challenges in aging and diversity research in the United States.

In 2016, the UC Davis Latino Aging Research Resource Center and UC Davis Alzheimer's Disease Center brought together experts from across the country to consolidate current knowledge and identify future directions in aging and diversity research. This report disseminates the research priorities that emerged from this conference, building on an earlier Gerontological Society of America preconference. We review key racial/ethnic differences in cognitive aging and dementia and identify current knowledge gaps in the field. We advocate for a systems-level framework for future research whereby environmental, sociocultural, behavioral, neuropathological, genetic, and psychometric levels of analysis are examined together to identify pathways and mechanisms that influence disparities. We then discuss steps to increase the recruitment and retention of racial/ethnic minorities in aging studies, as none of the recommendations will be possible without strong collaboration between racial/ethnic minority communities and researchers. This approach is consistent with the National Institute on Aging Health Disparities Research Framework.

Association Between Sustained Poverty and Changes in Body Mass Index, 1990-2015: The Coronary Artery Risk Development in Young Adults Study.

We sought to determine whether sustained poverty is associated with change in body mass index (BMI, calculated as weight (kg)/height (m)2) among 4,762 black and white adults from the Coronary Artery Risk Development in Young Adults study. Household income in the prior year and current BMI were measured at 7 visits between 1990 and 2015. Sustained poverty was the proportion of visits during which household income was below 200% of the federal poverty level (range, 0%-100%). Sustained poverty and BMI were time-updated. Mean age in 1990 was 30 years. In adjusted linear mixed-effects models, every 10% increase in sustained poverty was significantly associated with faster BMI growth among white men (0.004/year, 95% CI: 0.001, 0.008) and white women (0.003/year, 95% CI: 0.000, 0.006), and slower BMI growth among black men (-0.008/year, 95% CI: -0.010, -0.005) and black women (-0.003/year, 95% CI: -0.006, 0.000). In other words, being always versus never in poverty from 1990 to 2015 was predicted to result in greater BMI gain by 1.00 unit and 0.75 units among white men and women and less BMI gain by 2.0 units and 0.75 units among black men and women, respectively. Sustained poverty was a predictor of changes in BMI with differential associations according to race.

Can Survival Bias Explain the Age Attenuation of Racial Inequalities in Stroke Incidence?: A Simulation Study.

BACKGROUND: In middle age, stroke incidence is higher among black than white Americans. For unknown reasons, this inequality decreases and reverses with age. We conducted simulations to evaluate whether selective survival could account for observed age patterning of black-white stroke inequalities. METHODS: We simulated birth cohorts of 20,000 blacks and 20,000 whites with survival distributions based on US life tables for the 1919-1921 birth cohort. We generated stroke incidence rates for ages 45-94 years using Reasons for Geographic and Racial Disparities in Stroke (REGARDS) study rates for whites and setting the effect of black race on stroke to incidence rate difference (IRD) = 20/10,000 person-years at all ages, the inequality observed at younger ages in REGARDS. We compared observed age-specific stroke incidence across scenarios, varying effects of U, representing unobserved factors influencing mortality and stroke risk. RESULTS: Despite a constant adverse effect of black race on stroke risk, the observed black-white inequality in stroke incidence attenuated at older age. When the hazard ratio for U on stroke was 1.5 for both blacks and whites, but U only directly influenced mortality for blacks (hazard ratio for U on mortality =1.5 for blacks; 1.0 for whites), stroke incidence rates in late life were lower among blacks (average observed IRD = -43/10,000 person-years at ages 85-94 years versus causal IRD = 20/10,000 person-years) and mirrored patterns observed in REGARDS. CONCLUSIONS: A relatively moderate unmeasured common cause of stroke and survival could fully account for observed age attenuation of racial inequalities in stroke.

Factors Associated With Ischemic Stroke Survival and Recovery in Older Adults.

BACKGROUND AND PURPOSE: Little is known about factors that predispose older adults to poor recovery after a stroke. In this study, we sought to evaluate prestroke measures of frailty and related factors as markers of vulnerability to poor outcomes after ischemic stroke. METHODS: In participants aged 65 to 99 years with incident ischemic strokes from the Cardiovascular Health Study, we evaluated the association of several risk factors (frailty, frailty components, C-reactive protein, interleukin-6, and cystatin C) assessed before stroke with stroke outcomes of survival, cognitive decline (≥5 points on Modified Mini-Mental State Examination), and activities of daily living decline (increase in limitations). RESULTS: Among 717 participants with incident ischemic stroke with survival data, slow walking speed, low grip strength, and cystatin C were independently associated with shorter survival. Among participants <80 years of age, frailty and interleukin-6 were also associated with shorter survival. Among 509 participants with recovery data, slow walking speed, and low grip strength were associated with both cognitive and activities of daily living decline poststroke. C-reactive protein and interleukin-6 were associated with poststroke cognitive decline among men only. Frailty status was associated with activities of daily living decline among women only. CONCLUSIONS: Markers of physical function-walking speed and grip strength-were consistently associated with survival and recovery after ischemic stroke. Inflammation, kidney function, and frailty also seemed to be determinants of survival and recovery after an ischemic stroke. These markers of vulnerability may identify targets for differing pre and poststroke medical management and rehabilitation among older adults at risk of poor stroke outcomes.

Intima-Media Thickness and Cognitive Function in Stroke-Free Middle-Aged Adults: Findings From the Coronary Artery Risk Development in Young Adults Study.

BACKGROUND AND PURPOSE: The relationship between carotid artery intima-media thickness (IMT) and cognitive function in midlife remains relatively unexplored. We examined the association between IMT and cognitive function in a middle-aged epidemiological cohort of 2618 stroke-free participants. METHODS: At the year 20 visit (our study baseline), participants from the Coronary Artery Risk Development in Young Adults study had IMT measured by ultrasound at the common carotid artery. Five years later, participants completed a cognitive battery consisting of the Rey Auditory-Verbal Learning Test of verbal memory, the Digit Symbol Substitution Test of processing speed, and the Stroop test of executive function. We transformed cognitive scores into standardized z scores, with negative values indicating worse performance. RESULTS: Mean age at baseline was 45.3 years (SD, 3.6). Greater IMT (per 1 SD difference of 0.12 mm) was significantly associated with worse performance on all cognitive tests (z scores) in unadjusted linear regression models (verbal memory, -0.16; 95% confidence interval [CI], -0.20 to -0.13; processing speed, -0.23; 95% CI, -0.27 to -0.19; and executive function, -0.17; 95% CI, -0.20 to -0.13). In models adjusted for sociodemographics and vascular risk factors that lie earlier in the causal pathway, greater IMT remained negatively associated with processing speed (-0.06; 95% CI, -0.09 to -0.02; P, 0.003) and borderline associated with executive function (-0.03; 95% CI, -0.07 to 0.00; P, 0.07) but not with verbal memory. CONCLUSIONS: We observed an association between greater IMT and worse processing speed-a key component of cognitive functioning-at middle age above and beyond traditional vascular risk factors. Efforts targeted at preventing early stages of atherosclerosis may modify the course of cognitive aging.

Long-Term Depressive Symptom Trajectories and Midlife Cognition: The CARDIA Study.

BACKGROUND AND OBJECTIVES: The nature of associations between depressive symptoms and cognition early in the life course remains unclear, and racial differences in these associations are not well characterized. The aim of this study was to examine the relationship between trajectories of depressive symptom over 20 years, beginning in young adulthood, and cognitive functions in middle-age among Black and White adults. METHODS: We used prospective data from participants of the Coronary Artery Risk Development in Young Adults Study. Depressive symptoms were measured at 5 study visits between 1990 and 2010 using the Center for Epidemiologic Studies Depression scale. We used latent class group-based modeling to identify 4 trajectories: "persistently low," "persistently medium," "medium decreasing," and "high increasing" depressive symptoms. In 2015, cognitive function was measured using the Digit Symbol Substitution Test (DSST), Stroop test (reverse coded), and Rey Auditory-Verbal Learning Test (RAVLT).We excluded participants who missed the cognitive battery or had no depressive symptoms measurements, resulting in a total of 3,117 participants. All cognitive tests were standardized, and linear regression was used to relate depressive trajectories with 2015 cognitive functions. RESULTS: The mean [SD] baseline age was 30.1 [3.6] years, and 57% were female. The associations between depressive symptoms and cognition significantly differed by race (p < 0.05). Among Black individuals, compared with having "persistently low," having "medium decreasing," "persistently medium," or "high increasing" depressive symptoms were associated with worse verbal memory, processing speed, and executive function scores (RAVLT persistently medium vs low: ß = -0.30, 95% CI -0.48 to -0.12; and high increasing vs low: ß = -0.49, 95% CI -0.70 to -0.27; DSST persistently medium vs low: ß = -0.28, 95% CI -0.47 to -0.09; and high increasing vs low: ß = -0.64, 95% CI -0.87 to -0.42; Stroop persistently medium vs low: ß = -0.46, 95% CI -0.70 to -0.23; and high increasing vs low: ß = -0.76, 95% CI -1.04 to -0.47). Associations were slightly weaker among White individuals, but we still found that having 'high increasing' depressive symptoms was associated with worse verbal memory and processing speed scores (high increasing vs low: ß = -0.38, 95% CI -0.61 to -0.15; and ß = -0.40, 95% CI -0.63 to -0.18, respectively). DISCUSSION: Prolonged exposure to elevated depressive symptoms beginning in young adulthood may result in worse cognitive function over midlife. This association was stronger among Black adults.