Associations between sodium, potassium, and blood pressure: results from the Hispanic Community Health Study/Study of Latinos, a prospective cohort study.

BACKGROUND: Although the subject of numerous studies, the associations between dietary sodium, potassium, and the ratio of dietary sodium to potassium with blood pressure are not clear-cut. In addition, there is a paucity of research on these relationships in prospective cohort studies with representation from diverse Hispanic/Latino adults. OBJECTIVES: To evaluate the associations between dietary intake of sodium, potassium, and the ratio of dietary sodium to potassium and blood pressure in a diverse sample of Hispanics living in the United States. METHODS: This analysis included 11,429 Hispanic/Latino participants of the prospective cohort Hispanic Community Health Study/Study of Latinos recruited between 2008 and 2011 in visit 1 who participated in a follow-up visit in 2014-2017. Dietary sodium and potassium intakes were averaged from 2 interviewer-administered 24-h diet recalls collected at visit 1. At both visits, blood pressure was measured 3 times in a seated position and averaged. We assessed the relationship between dietary sodium, potassium, and the sodium-to-potassium ratio with changes in systolic and diastolic blood pressure using survey-weighted multivariable-adjusted regression models. RESULTS: At visit 1, the mean age was 41 y, and the mean sodium intake was 3203 mg/d. Each 500 mg/d sodium increment in intake was associated with an increase in systolic blood pressure (ß: 0.35 [mmHg]; 95% confidence interval: 0.06, 0.63) and diastolic blood pressure (ß: 0.45 [mmHg]; 95% confidence interval: 0.08, 0.82). Dietary potassium and the molar ratio of dietary sodium to potassium were not associated with changes in systolic or diastolic blood pressure. CONCLUSIONS: Among a large sample of diverse United States Hispanic/Latino adults, higher sodium intake was associated with small increases in systolic blood pressure over 6 y. This research underscores the importance of dietary sodium reduction in maintaining lower blood pressure.

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.

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.

Food Insecurity, Memory, and Dementia Among US Adults Aged 50 Years and Older.

Importance: Despite existing federal programs to increase access to food, food insecurity is common among US older adults. Food insecurity may affect Alzheimer disease and Alzheimer disease-related dementias via multiple mechanisms, yet there is almost no quantitative research evaluating this association. Objective: To examine whether food insecurity in older adults is associated with later-life cognitive outcomes. Design, Setting, and Participants: This cohort study of US residents aged 50 years and older from the US Health and Retirement Study was restricted to respondents with food insecurity data in 2013 and cognitive outcome data between calendar years 2014 and 2018. Analyses were conducted from June 1 to September 22, 2023. Exposure: Food insecurity status in 2013 was assessed using the validated US Department of Agriculture 6-item Household Food Security Module. Respondents were classified as being food secure, low food secure, and very low food secure. Main Outcomes and Measures: Outcomes were dementia probability and memory score (standardized to 1998 units), estimated biennially between 2014 and 2018 using a previously validated algorithm. Generalized estimation equations were fit for dementia risk and linear mixed-effects models for memory score, taking selective attrition into account through inverse probability of censoring weights. Results: The sample consisted of 7012 participants (18 356 person-waves); mean (SD) age was 67.7 (10.0) years, 4131 (58.9%) were women, 1136 (16.2%) were non-Hispanic Black, 4849 (69.2%) were non-Hispanic White, and mean (SD) duration of schooling was 13.0 (3.0) years. Compared with food-secure older adults, experiencing low food security was associated with higher odds of dementia (odds ratio, 1.38; 95% CI, 1.15-1.67) as was experiencing very low food security (odds ratio, 1.37; 95% CI, 1.11-1.59). Low and very low food security was also associated with lower memory levels and faster age-related memory decline. Conclusions and Relevance: In this cohort study of older US residents, food insecurity was associated with increased dementia risk, poorer memory function, and faster memory decline. Future studies are needed to examine whether addressing food insecurity may benefit brain health.

Associations of Food Insecurity and Memory Function Among Middle to Older-Aged Adults in the Health and Retirement Study.

Importance: Food insecurity is a leading public health issue in the US. Research on food insecurity and cognitive aging is scarce, and is mostly cross-sectional. Food insecurity status and cognition both can change over the life course, but their longitudinal relationship remains unexplored. Objective: To examine the longitudinal association between food insecurity and changes in memory function during a period of 18 years among middle to older-aged adults in the US. Design, Setting, and Participants: The Health and Retirement Study is an ongoing population-based cohort study of individuals aged 50 years or older. Participants with nonmissing information on their food insecurity in 1998 who contributed information on memory function at least once over the study period (1998-2016) were included. To account for time-varying confounding and censoring, marginal structural models were created, using inverse probability weighting. Data analyses were conducted between May 9 and November 30, 2022. Main outcomes and Measures: In each biennial interview, food insecurity status (yes/no) was assessed by asking respondents whether they had enough money to buy food or ate less than they felt they should. Memory function was a composite score based on self-completed immediate and delayed word recall task of a 10-word list and proxy-assessed validated instruments. Results: The analytic sample included 12 609 respondents (mean [SD] age, 67.7 [11.0] years, 8146 [64.60%] women, 10 277 [81.51%] non-Hispanic White), including 11 951 food-secure and 658 food-insecure individuals in 1998. Over time, the memory function of the food-secure respondents decreased by 0.045 SD units annually (ß for time, -0.045; 95% CI, -0.046 to -0.045 SD units). The memory decline rate was faster among food-insecure respondents than food-secure respondents, although the magnitude of the coefficient was small (ß for food insecurity × time, -0.0030; 95% CI, -0.0062 to -0.00018 SD units), which translates to an estimated 0.67 additional (ie, excess) years of memory aging over a 10-year period for food-insecure respondents compared with food-secure respondents. Conclusions and Relevance: In this cohort study of middle to older-aged individuals, food insecurity was associated with slightly faster memory decline, suggesting possible long-term negative cognitive function outcomes associated with exposure to food insecurity in older age.

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.

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.

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.

Depressive symptoms mediate the relationship between sustained food insecurity and cognition: a causal mediation analysis.

PURPOSE: This study aimed to investigate the association of change in food insecurity over time with cognitive function in midlife, and whether depressive symptoms mediated that relationship. METHODS: We used longitudinal data from the Coronary Artery Risk Development in Young Adults study. Change in food insecurity in 2000-2005 was coded as "persistently food-secure," "persistently food-insecure," "became food-insecure," and "became food-secure." Depressive symptoms were measured in 2010, and cognitive function was measured in 2015. Multivariable linear regression controlled for sociodemographic and cardiovascular health factors was used. We also conducted causal mediation analysis. RESULTS: Our study population included 2448 participants (57.23% female and 43.18% Black, mean age = 40.31 in 2000). Compared with persistent food security, persistently and became food-insecure were associated with worse cognition, particularly with processing speed (ßpersistent = -0.20 standard unit, 95% CI = -0.36, -0.04; ßbecame = -0.17, 95% CI = -0.31, -0.03), and these associations appeared mediated by depressive symptoms (proportion-mediated = 14% for persistently food-insecure and 18% for became food-insecure). CONCLUSIONS: Persistent and transition to food insecurity were associated with worse cognition, both directly and indirectly through increasing depressive symptoms. Targeting food insecurity or depressive symptoms among persistently or became food-insecure individuals may have the potential to slow premature cognitive aging.

Racial Differences in Employment and Poverty Histories and Health in Older Age.

INTRODUCTION: Black Americans encounter more barriers in the job market and earn less than White Americans. However, the extent to which racial disparities in employment and poverty histories impact health is not fully understood. This study characterized employment‒poverty histories for Black and White middle-aged adults and examined their association with health. METHODS: Respondents born in 1948-1953 and enrolled in the 2004 Health and Retirement Study (NBlack=555, NWhite=2,209) were included. Sequence analysis grouped respondents with similar employment‒poverty trajectories from 2004 to 2016, and confounder-adjusted regression analyses estimated the associations between these trajectories and health in 2018. Analyses were conducted in 2021-2022. RESULTS: More than 23% of Black respondents experienced both employment and poverty fluctuations, including bouts of extreme poverty (<50% of the federal poverty threshold), whereas no trajectory for White respondents included extreme poverty. Adversities in employment‒poverty were associated with worse health. For example, among Black respondents, those who experienced both employment and poverty fluctuations had worse cognition than those employed and not poor (ß= -0.55 standardized units, 95% CI= -0.81, -0.30). Similarly, among White respondents, those who experienced employment fluctuations had worse cognition than those employed (ß= -0.35, 95% CI= -0.46, -0.24). Notably, the employed and not poor trajectory was associated with worse survival among Black respondents than among White respondents. CONCLUSIONS: Employment fluctuations were associated with worse health, especially cognitive function, where the association was stronger among Black Americans who experienced both employment fluctuations and poverty. Findings highlight the importance of enhancing employment stability and of antipoverty programs, especially for Black Americans.

Associations of Religious Service Attendance With Cognitive Function in Midlife: Findings From The CARDIA Study.

OBJECTIVES: Growing evidence suggests that religiosity is an important social determinant of health, including cognitive health. Yet most prior work focused on older adults or was conducted in racially and denominationally homogeneous regional samples. This study investigates the association of religious service attendance in midlife with cognitive function later in midlife. METHODS: Using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a racially and geographically diverse prospective cohort study, we explored the association of religious service attendance in midlife with cognitive function 5 years later. Cognitive function was measured using four cognitive tests administered by CARDIA technicians. Multivariable linear regression was used for analyses. Primary analyses controlled for sociodemographics, physical health, depression, and prior religious involvement. Sensitivity analyses additionally controlled for baseline cognition and social support. RESULTS: Our study population included 2,716 participants (57.2% female, 44.9% Black, and mean age 50). In primary analyses, attending services more than weekly (compared to never) in midlife was associated with better global cognition (ß = 0.14 standard deviations, 95% [confidence interval] CI = 0.02, 0.26) and verbal memory (ß = 0.17 standard deviations, 95% CI = 0.04, 0.30), but not with processing speed (ß = 0.04 standard deviations, 95% CI = -0.08, 0.16). A reverse association was observed with executive function (ß = -0.16 standard deviations, 95% CI = -0.30, -0.02). Most findings persisted in analyses accounting for loss to follow-up via inverse probability weighting. DISCUSSION: Our findings suggest that frequent involvement in religious services at midlife is associated with better global cognition and verbal memory but worse executive function. There was no association with processing speed.

Association Between Supplemental Nutrition Assistance Program Use and Memory Decline: Findings From the Health and Retirement Study.

BACKGROUND AND OBJECTIVES: Studies on the effect of the Supplemental Nutrition Assistance Program (SNAP) on the cognitive health of older adults are scarce. We sought to examine the associations between SNAP use and memory decline among SNAP-eligible US older adults. METHODS: Participants aged 50+ years and SNAP-eligible in 1996 from the Health and Retirement Study were included. Participants' SNAP eligibility was constructed using federal criteria. Participants also self-reported whether they used SNAP. Memory function was assessed biennially from 1996 through 2016 using a composite score. To account for preexisting differences in characteristics between SNAP users and nonusers, we modeled the probability of SNAP use using demographic and health covariates. Using linear mixed-effects models, we then modeled trajectories of memory function for SNAP users and nonusers using inverse probability (IP) weighting and propensity score (PS) matching techniques. In all models, we accounted for study attrition. RESULTS: Of the 3,555 SNAP-eligible participants, a total of 15.7% were SNAP users. At baseline, SNAP users had lower socioeconomic status and a greater number of chronic conditions than nonusers and were more likely to be lost to follow-up. Our multivariable IP-weighted models suggested that SNAP users had worse memory scores at baseline but slower rates of memory decline compared with nonusers (the annual decline rate is -0.038 standardized units [95% CI = -0.044 to -0.032] for users and -0.046 [95% CI = -0.049 to -0.043] for nonusers). Results were slightly stronger from the PS-matched sample (N = 1,014) (the annual decline rate was -0.046 units [95% CI = -0.050 to -0.042] for users and -0.060 units [95% CI = -0.064 to -0.056] for nonusers). Put in other words, our findings suggested that SNAP users had approximately 2 fewer years of cognitive aging over a 10-year period compared with nonusers. DISCUSSION: After accounting for preexisting differences between eligible SNAP users and nonusers as well as differential attrition, we find SNAP use to be associated with slower memory function decline.

Associations Between Cognitive Functioning and Mortality in a Population-Based Sample of Older United States Adults: Differences by Sex and Education.

Objective: To determine whether cognition is associated with mortality among older US adults. Methods: We studied 5,989 National Health and Nutrition Examination Survey participants age 60+ in years 1999-2014 with mortality follow-up through 2015. Cognitive function was measured in one standard deviation decrements using the Digit Symbol Substitution Test (DSST), Animal Fluency (AnFl), and two Consortium to Establish a Registry for Alzheimer's Disease (CERAD) tests. Results: Each decrement in cognitive function was associated with increased risk of mortality overall (DSST HR: 1.36, 95% CI: 1.25, 1.48), among women only (AnFl: 1.51, 95% CI: 1.02, 2.24), and among those with less than a high school education only (AnFl HR: 1.46, 95% CI: 1.09, 1.97; CERAD-WL HR: 1.34, 95% CI: 1.07, 1.67; and CERAD-DR HR: 1.38, 95% CI: 1.05, 1.82). Discussion: Among US adults, lower cognitive functioning was associated with mortality; associations were stronger among women and those with less education.

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.

Statins and Cognitive Decline in the Cardiovascular Health Study: A Comparison of Different Analytical Approaches.

BACKGROUND: Despite their well-established benefits for the prevention of cardiovascular disease, robust evidence on the effects of statins on cognition is largely inconclusive. We apply various study designs and analytical approaches to mimic randomized controlled trial effects from observational data. METHODS: We used observational data from 5 580 participants enrolled in the Cardiovascular Health Study from 1989/1990 to 1999/2000. We conceptualized the cohort as an overlapping sequence of nonrandomized trials. We compared multiple selection (eligible population, prevalent users, new users) and analytic approaches (multivariable adjustment, inverse-probability treatment weights, propensity score matching) to evaluate the association between statin use and 5-year change in global cognitive function, assessed using the Modified Mini-Mental State Examination (3MSE). RESULTS: When comparing prevalent users to nonusers (N = 2 772), statin use was associated with slower cognitive decline over 5 years (adjusted annual change in 3MSE = 0.34 points/year; 95% CI: 0.05-0.63). Compared to prevalent user design, estimates from new user designs (eg, comparing eligible statin initiators to noninitiators) were attenuated showing either null or negative association, though not significant. For example, in a propensity score-matched sample of statin-eligible individuals (N = 454), the annual 3MS change comparing statin initiators to noninitiators was -0.21 points/year (95% CI: -0.81 to 0.39). CONCLUSIONS: The association of statin use and cognitive decline is attenuated toward the null when using rigorous analytical approaches that more closely mimic randomized controlled trials. Point estimates, even within the same study, may vary depending on the analytical methods used. Further studies that leverage natural or quasi experiments around statin use are needed to replicate our findings.

Intergenerational educational mobility and type 2 diabetes in the Sacramento Area Latino Study on Aging.

PURPOSE: United States (US) Latinos have the lowest educational attainment of any US racial/ethnic group, which may contribute to their disparate burden of Type 2 Diabetes. Herein, we aimed to examine the association between intergenerational educational mobility and Type 2 Diabetes among US Latino adults. METHODS: We used data from the Niños Lifestyle and Diabetes Study (2013-2014) and the Sacramento Area Latino Study on Aging (1998-1999) to link 616 adult Latino children to their parents. Model-based standardization and robust Poisson regression were used to estimate the prevalence of prediabetes, Type 2 Diabetes, treatment and glycemic control, and describe their associations with intergenerational educational mobility. RESULTS: Adult children with stable high intergenerational educational attainment had a higher prevalence of prediabetes (Prevalence Ratio, PR=1.58; 95% Confidence Interval, CI=1.08, 2.34) and lower prevalence of Type 2 Diabetes (PR=0.64, CI=0.41, 0.99), as compared to those who experienced low educational attainment across generations. Downward mobility was associated with a higher prevalence of prediabetes (PR=1.54, CI=1.06, 2.23) and worse glycemic control (PR=2.20, CI=1.13, 4.30), and upward mobility was associated with a lower prevalence of Type 2 Diabetes (PR=0.39, CI=0.22, 0.70). CONCLUSIONS: Our findings from a predominantly Mexican-heritage community suggest that higher education across generations may buffer individuals from glycemic dysregulation. As such, higher education may be a promising public health target to address the rising burden of Type 2 Diabetes in the US.

Associations Between 20-Year Lipid Variability Throughout Young Adulthood and Midlife Cognitive Function and Brain Integrity.

BACKGROUND: Little is known about long-term lipid variability in young adulthood in relation to cognitive function and brain integrity in midlife. METHOD: We studied 3 328 adults from the Coronary Artery Risk Development in Young Adults. We defined low- and high-density lipoprotein (LDL and HDL) variability as the intraindividual standard deviation of lipid measurements over 20 years of young adulthood (1985-2005). Cognitive tests were administered in 2010. Brain scans were performed in 2010 on 714 participants. To facilitate comparison, cognitive tests and brain metrics were z-scored. RESULTS: Mean age at baseline was 25.4 years. Higher 20-year LDL variability was associated with worse verbal memory in midlife (ß = -0.25, 95% CI: -0.42, -0.08), adjusted for important covariates. Higher 20-year HDL variability was associated with worse processing speed in midlife (ß = -0.80, 95% CI: -1.18, -0.41) and brain integrity, for example, smaller total brain volume (ß = -0.58, 95% CI: -0.82, -0.34) and worse total brain fractional anisotropy (ß = -1.13, 95% CI: -1.87, -0.39). CONCLUSIONS: Higher long-term lipid variability in adulthood was associated with worse cognition and brain integrity in midlife, in a relatively young cohort.