Representativeness of Participants in the ACCORD Trial Compared to Middle-aged and Older Adults Living with Diabetes in the United States.

BACKGROUND: We evaluated whether participants in the landmark Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial represent US adults aged ≥40 with diabetes. METHODS: Using the nationally representative 2017-2020 prepandemic National Health and Nutrition Examination Survey data, we made operational definitions of ACCORD eligibility criteria. We calculated the percentage of individuals aged ≥40 with diabetes and HbA1c ≥ 6.0% or ≥ 7.5% who met operational ACCORD eligibility criteria. RESULTS: Applying survey sampling weights to 715 National Health and Nutrition Examination Survey participants aged ≥40 with diabetes and HbA1c ≥ 6.0% (representing 29,717,406 individuals), 12% (95% confidence interval [CI] = 8%, 18%) met the operational ACCORD eligibility criteria. Restricting to HbA1c ≥ 7.5%, 39% (95% CI = 28%, 51%) of respondents met the operational ACCORD eligibility criteria. CONCLUSIONS: ACCORD represented a minority of US middle-aged and older adults with diabetes. Given the differential risk profile between ACCORD participants and the general population with diabetes, extrapolating the trial findings may not be appropriate.

Target trial emulation using cohort studies: estimating the effect of antihypertensive medication initiation on incident dementia.

BACKGROUND: Observational studies link high midlife systolic blood pressure to increased dementia risk. However, synthesis of evidence from randomized controlled trials has not definitively demonstrated that antihypertensive medication use reduces dementia risk. Here, we emulate target trials of antihypertensive medication initiation on incident dementia using three cohort studies, with attention to potential violations of necessary assumptions. METHODS: We emulated trials of antihypertensive medication initiation on incident dementia using data from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Health and Retirement Study (HRS). We used data-driven methods to restrict participants to initiators and non-initiators with overlap in propensity scores and positive control outcomes to look for violations of positivity and exchangeability assumptions. RESULTS: Analyses were limited by the small number of cohort participants who met eligibility criteria. Associations between antihypertensive medication initiation and incident dementia were inconsistent and imprecise (ARIC: HR = 0.30 [0.05, 1.93]; CHS: HR = 0.66 [0.27, 1.64]; HRS: HR = 1.09 [0.75, 1.59]). More stringent propensity score restriction had little effect on findings. Sensitivity analyses using a positive control outcome unexpectedly suggested antihypertensive medication initiation increased risk of coronary heart disease in all three samples. CONCLUSIONS: Positive control outcome analyses suggested substantial residual confounding in effect estimates from our target trials, precluding conclusions about the impact of antihypertensive medication initiation on dementia risk through target trial emulation. Formalized processes for identifying violations of necessary assumptions will strengthen confidence in target trial emulation and avoid inappropriate confidence in emulated trial results.

Educational Attainment and Dementia: Mediation by Mid-Life Vascular Risk Factors.

INTRODUCTION: Lower education is associated with higher burden of vascular risk factors in mid-life and higher risk of dementia in late life. We aim to understand the causal mechanism through which vascular risk factors potentially mediate the relationship between education and dementia. METHODS: In a cohort of 13,368 Black and White older adults in the Atherosclerosis Risk in Communities Study, we assessed the relationship between education (grade school, high school without graduation, high school graduate or equivalent, college, graduate/professional school) and dementia among all participants and among those with incident stroke. Cox models were adjusted for age, race-center (a variable stratified by race and field center), sex, apolipoprotein E (APOE) ε4 genotype, and family history of cardiovascular disease. Causal mediation models assessed mediation by mid-life systolic blood pressure, fasting blood glucose, body mass index, and smoking. RESULTS: More education was associated with 8 to 44% lower risk of dementia compared to grade school-level education in a dose-response pattern, while the relationship between education and post-stroke dementia was not statistically significant. Up to 25% of the association between education and dementia was mediated through mid-life vascular risk factors, with a smaller percentage mediated for lower levels of education. INTERPRETATION: A substantial proportion of the relationship between education and dementia was mediated through mid-life vascular risk factors. However, risk factor modification is unlikely to fully address the large educational disparities in dementia risk. Prevention efforts must also address disparities in socioeconomic resources leading to divergent early-life education and other structural determinants of mid-life vascular risk factors. ANN NEUROL 2023;94:13-26.

Association of midlife air pollution exposures and residential road proximity with incident dementia: The Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Increasing evidence links higher air pollution exposures to increased risk of cognitive impairment. While midlife risk factors are often most strongly linked to dementia risk, few studies have considered associations between midlife roadway proximity or ambient air pollution exposure and incident dementia decades later, in late life. OBJECTIVES: Our objective was to determine if midlife exposures to ambient air pollution or roadway proximity are associated with increased risk of dementia in the Atherosclerosis Risk in Communities (ARIC) study over up to 29 years of follow-up. METHODS: Our eligible sample included Black and White ARIC participants without dementia at Visit 2 (1990-1992). Participants were followed through Visit 7 (2018-2019), with dementia status and onset date defined based on formal dementia ascertainment at study visits, informant interviews, and surveillance efforts. We used adjusted Weibull survival models to assess the associations of midlife ambient air pollution and road proximity with incident dementia. RESULTS: The median age at baseline (1990-1992, Visit 2) of the 12,700 eligible ARIC participants was 57.0 years; 56.0% were female, 24.2% were Black, and 78.9% had at least a high school education. Over up to 29 years of follow-up, 2511 (19.8%) persons developed dementia. No associations were found between ambient air pollutants and proximity to major roadways with risk of incident dementia. In exploratory analyses, living closer to roadways in midlife increased dementia risk in individuals younger at baseline and those without midlife hypertension, and there was evidence of increased risk of dementia with increased midlife exposure to NOx, several PM2.5 components, and trace metals among those with diabetes in midlife. CONCLUSIONS: Midlife exposure to ambient air pollution and midlife roadway proximity was not associated with dementia risk over decades of follow-up. Further investigation to explore potential for greater susceptibility among specific subgroups identified here is needed.

A comparison of PM2.5 exposure estimates from different estimation methods and their associations with cognitive testing and brain MRI outcomes.

BACKGROUND: Reported associations between particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5) and cognitive outcomes remain mixed. Differences in exposure estimation method may contribute to this heterogeneity. OBJECTIVES: To assess agreement between PM2.5 exposure concentrations across 11 exposure estimation methods and to compare resulting associations between PM2.5 and cognitive or MRI outcomes. METHODS: We used Visit 5 (2011-2013) cognitive testing and brain MRI data from the Atherosclerosis Risk in Communities (ARIC) Study. We derived address-linked average 2000-2007 PM2.5 exposure concentrations in areas immediately surrounding the four ARIC recruitment sites (Forsyth County, NC; Jackson, MS; suburbs of Minneapolis, MN; Washington County, MD) using 11 estimation methods. We assessed agreement between method-specific PM2.5 concentrations using descriptive statistics and plots, overall and by site. We used adjusted linear regression to estimate associations of method-specific PM2.5 exposure estimates with cognitive scores (n = 4678) and MRI outcomes (n = 1518) stratified by study site and combined site-specific estimates using meta-analyses to derive overall estimates. We explored the potential impact of unmeasured confounding by spatially patterned factors. RESULTS: Exposure estimates from most methods had high agreement across sites, but low agreement within sites. Within-site exposure variation was limited for some methods. Consistently null findings for the PM2.5-cognitive outcome associations regardless of method precluded empirical conclusions about the potential impact of method on study findings in contexts where positive associations are observed. Not accounting for study site led to consistent, adverse associations, regardless of exposure estimation method, suggesting the potential for substantial bias due to residual confounding by spatially patterned factors. DISCUSSION: PM2.5 estimation methods agreed across sites but not within sites. Choice of estimation method may impact findings when participants are concentrated in small geographic areas. Understanding unmeasured confounding by factors that are spatially patterned may be particularly important in studies of air pollution and cognitive or brain health.

Estimated effects of amyloid reduction on cognitive change: A Bayesian update across a range of priors.

INTRODUCTION: The results of the CLARITY-AD, GRADUATE I and II, and TRAILBLAZER-ALZ 2 trials have rekindled discussion on the impact of amyloid-targeting drugs. We use a Bayesian approach to quantify how rational observers would have updated their prior beliefs based on new trial results. METHODS: We used publicly available data from the CLARITY-AD, GRADUATE I and II, and TRAILBLAZER-ALZ 2 trials to estimate the effect of reducing amyloid on the clinical dementia rating scale, sum of boxes (CDR-SB) score. A range of prior positions were then updated according to Bayes' theorem using these estimates. RESULTS: After updating with new trial data, a wide range of starting positions resulted in credible intervals that did not include no effect of amyloid reduction on CDR-SB score. DISCUSSION: For a range of starting beliefs and assuming the veracity of the underlying data, rational observers would conclude there is a small benefit of amyloid reductions on cognition. This benefit must be weighed against opportunity cost and side-effect risk. HIGHLIGHTS: The results of recent trials of amyloid-targeting drugs have rekindled discussion on the impact of amyloid reductions achieved with amyloid-targeting drugs on cognition. Prior to the announcement of trial results, beliefs about the effects of altering amyloid levels varied. For a range of starting beliefs, one would conclude there is a small benefit of amyloid reductions due to amyloid-targeting drugs on cognition. The perceived value of individual drugs must balance the magnitude of this benefit against opportunity cost and risk of side effects.

Correlates of missed or late versus timely diagnosis of dementia in healthcare settings.

INTRODUCTION: There is limited evidence about factors related to the timeliness of dementia diagnosis in healthcare settings. METHODS: In five prospective cohorts at Rush Alzheimer's Disease Center, we identified participants with incident dementia based on annual assessments and examined the timing of healthcare diagnoses in Medicare claims. We assessed sociodemographic, health, and psychosocial correlates of timely diagnosis. RESULTS: Of 710 participants, 385 (or 54%) received a timely claims diagnosis within 3 years prior to or 1 year following dementia onset. In logistic regressions accounting for demographics, we found Black participants (odds ratio [OR] = 2.15, 95% confidence interval [CI]: 1.21 to 3.82) and those with better cognition at dementia onset (OR = 1.48, 95% CI: 1.10 to 1.98) were at higher odds of experiencing a diagnostic delay, whereas participants with higher income (OR = 0.89, 95% CI: 0.81 to 0.97) and more comorbidities (OR = 0.94, 95% CI: 0.89 to 0.98) had lower odds. DISCUSSION: We identified characteristics of individuals who may miss the optimal window for dementia treatment and support. HIGHLIGHTS: We compared the timing of healthcare diagnosis relative to the timing of incident dementia based on rigorous annual evaluation. Older Black adults with lower income, higher cognitive function, and fewer comorbidities were less likely to be diagnosed in a timely manner by the healthcare system.

Comparison of Imputation Strategies for Incomplete Longitudinal Data in Life-Course Epidemiology.

Incomplete longitudinal data are common in life-course epidemiology and may induce bias leading to incorrect inference. Multiple imputation (MI) is increasingly preferred for handling missing data, but few studies explore MI-method performance and feasibility in real-data settings. We compared 3 MI methods using real data under 9 missing-data scenarios, representing combinations of 10%, 20%, and 30% missingness and missing completely at random, at random, and not at random. Using data from Health and Retirement Study (HRS) participants, we introduced record-level missingness to a sample of participants with complete data on depressive symptoms (1998-2008), mortality (2008-2018), and relevant covariates. We then imputed missing data using 3 MI methods (normal linear regression, predictive mean matching, variable-tailored specification), and fitted Cox proportional hazards models to estimate effects of 4 operationalizations of longitudinal depressive symptoms on mortality. We compared bias in hazard ratios, root mean square error, and computation time for each method. Bias was similar across MI methods, and results were consistent across operationalizations of the longitudinal exposure variable. However, our results suggest that predictive mean matching may be an appealing strategy for imputing life-course exposure data, given consistently low root mean square error, competitive computation times, and few implementation challenges.

Investigation of the association of military employment and Parkinson's disease with a validated Parkinson's disease case-finding strategy.

INTRODUCTION: Persons with military involvement may be more likely to have Parkinson's disease (PD) risk factors. As PD is rare, case finding remains a challenge, contributing to our limited understanding of PD risk factors. Here, we explore the validity of case-finding strategies and whether military employment is associated with PD. MATERIALS AND METHODS: We identified Adult Changes in Thought (ACT) study participants reporting military employment as their longest or second longest occupation. We used self-report and prescription fills to identify PD cases and validated this case-finding approach against medical record review. RESULTS: At enrollment, 6% of 5,125 eligible participants had military employment and 1.8% had prevalent PD; an additional 3.5% developed PD over follow-up (mean: 8.3 years). Sensitivity of our case-finding approach was higher for incident (80%) than prevalent cases (54%). Specificity was high (>97%) for both. Military employment was not associated with prevalent PD. Among nonsmokers, point estimates suggested an increased risk of incident PD with military employment, but the result was non-significant and based on a small number of cases. CONCLUSIONS: Self-report and prescription medications can accurately identify incident PD cases relative to the reference method of medical record review. We found no association between military employment and PD.

The Associations of Dietary Copper With Cognitive Outcomes.

Dietary copper intake may be associated with cognitive decline and dementia. We used data from 10,269 participants of the Atherosclerosis Risks in Communities Study to study the associations of dietary copper intake with 20-year cognitive decline and incident dementia. Dietary copper intake from food and supplements was quantified using food frequency questionnaires. Cognition was assessed using 3 cognitive tests at study visits; dementia was ascertained at study visits and via surveillance. Multiple imputation by chained equations was applied to account for the missing information of cognitive function during follow-up. Survival analysis with parametric models and mixed-effect models were used to estimate the associations for incident dementia and cognitive decline, respectively. During 20 years of follow-up (1996-1998 to 2016-2017), 1,862 incident cases of dementia occurred. Higher intake of dietary copper from food was associated with higher risk of incident dementia among those with high intake of saturated fat (hazard ratio = 1.49, 95% confidence interval: 1.04, 1.95). Higher intake of dietary copper from food was associated with greater decline in language overall (beta = -0.12, 95% confidence interval: -0.23, -0.02). Therefore, a diet high in copper, particularly when combined with a diet high in saturated fat, may increase the risk of cognitive impairment.

Closing the Gap Between Observational Research and Randomized Controlled Trials for Prevention of Alzheimer Disease and Dementia.

Although observational studies have identified modifiable risk factors for Alzheimer disease and related dementias (ADRD), randomized controlled trials (RCTs) of risk factor modification for ADRD prevention have been inconsistent or inconclusive. This finding suggests a need to improve translation between observational studies and RCTs. However, many common features of observational studies reduce their relevance to designing related RCTs. Observational studies routinely differ from RCTs with respect to eligibility criteria, study population, length of follow-up, treatment conditions, outcomes, and effect estimates. Using the motivating example of blood pressure reduction for ADRD prevention, we illustrate the need for a tighter connection between observational studies and RCTs, discuss barriers to using typically reported observational evidence in developing RCTs, and highlight methods that may be used to make observational research more relevant to clinical trial design. We conclude that the questions asked and answered by observational research can be made more relevant to clinical trial design and that better use of observational data may increase the likelihood of successful, or at least definitive, trials. Although we focus on improving translation of observational studies on risk factors for ADRD to RCTs in ADRD prevention, the overarching themes are broadly applicable to many areas of biomedical research.

Incidence of dementia in a Brazilian population: The Tremembé Epidemiologic Study.

INTRODUCTION: Few dementia incidence studies have been performed in Latin America. We aimed to provide the incidence of dementia in a Brazilian community-dwelling elderly population. METHODS: This study was conducted in urban and rural areas of Tremembé. The 520 participants without dementia at baseline were invited to participate in the follow-up. RESULTS: After a median follow-up of 5 years, the incidence rate of dementia was 26.1 per 1000 person-years (PY) (95% confidence interval  = 18.7-36.6/1000PY). This rate increased exponentially with age (8.3/1000PY for 60- to 64-year-olds to 110.2/1000PY for ≥80-year-olds) and lower education (10.5/1000PY for > 8 years of education to 59.2/1000PY for illiterates). Higher dementia risk was found among individuals with cognitive impairment no dementia at baseline. DISCUSSION: The dementia incidence rate found was higher than in other countries in people under 65 years. Higher incidence in younger individuals is expected in developing countries probably due to low education and a high burden of cardiovascular diseases.

Post-stroke cognitive impairment and the risk of stroke recurrence and death in patients with insulin resistance.

OBJECTIVE: Post-stroke cognitive impairment (PSCI) is associated with etiology, severity, and functional outcome of stroke. The risks of recurrent stroke and death in patients with PSCI and insulin resistance (IR) is unknown. The goal of this study was to determine whether global and domain-specific cognitive impairment after stroke in patients with IR was associated with recurrent stroke and death. MATERIALS AND METHODS: We studied patients with recent stroke or transient ischemic attack (TIA) and IR with a baseline Modified Mini-Mental State Examination (3MS) cognitive exam at median of 79 days after stroke. We considered a baseline score of ≤ 88 on the 3MS to indicate global cognitive impairment, and domain-specific summary scores in the lowest quartile to indicate language, attention, orientation, memory and visuospatial impairments. The primary endpoint was fatal or non-fatal recurrent stroke, and the secondary endpoints were all-cause mortality, and fatal or non-fatal myocardial infarction (MI). RESULTS: Among studied n = 3,338 patients 13.6% had global cognitive impairment. During the median 4.96 years of follow-up, 7.4% patients experienced recurrent stroke, 3.5% MI, and 7.3% died. In the fully adjusted model, impairment in language (HR 1.35; 95% CI 1.01-1.81) and orientation (HR 1.41; 95% CI: 1.06-1.87) were associated with a higher risk of recurrent stroke, while attention impairment was associated with all-cause mortality (HR 1.34; 95% CI: 1.01-1.78). DISCUSSION/CONCLUSION: In patients with recent stroke/TIA and IR, post-stroke language and orientation impairments independently predicted recurrent stroke, while attention deficit was associated with increased risk of all-cause mortality.

Proof of Concept Example for Use of Simulation to Allow Data Pooling Despite Privacy Restrictions.

BACKGROUND: Integrating results from multiple samples is often desirable, but privacy restrictions may preclude full data pooling, and most datasets do not include fully harmonized variable sets. We propose a simulation-based method leveraging partial information across datasets to guide creation of synthetic data based on explicit assumptions about the underlying causal structure that permits pooled analyses that adjust for all desired confounders in the context of privacy restrictions. METHODS: This proof-of-concept project uses data from the Health and Retirement Study (HRS) and Atherosclerosis Risk in Communities (ARIC) study. We specified an estimand of interest and a directed acyclic graph (DAG) summarizing the presumed causal structure for the effect of glycated hemoglobin (HbA1c) on cognitive change. We derived publicly reportable statistics to describe the joint distribution of each variable in our DAG. These summary estimates were used as data-generating rules to create synthetic datasets. After pooling, we imputed missing covariates in the synthetic datasets and used the synthetic data to estimate the pooled effect of HbA1c on cognitive change, adjusting for all desired covariates. RESULTS: Distributions of covariates and model coefficients and associated standard errors for our model estimating the effect of HbA1c on cognitive change were similar across cohort-specific original and preimputation synthetic data. The estimate from the pooled synthetic incorporates control for confounders measured in either original dataset. DISCUSSION: Our approach has advantages over meta-analysis or individual-level pooling/data harmonization when privacy concerns preclude data sharing and key confounders are not uniformly measured across datasets.

Cognitive Impairment after Lacunar Stroke and the Risk of Recurrent Stroke and Death.

INTRODUCTION: Patients with poststroke cognitive impairment appear to be at higher risk of recurrent stroke and death. However, whether cognitive impairment after lacunar stroke is associated with recurrent stroke and death remains unclear. We assessed whether global or domain-specific cognitive impairment after lacunar stroke is associated with recurrent stroke and death. METHODS: We considered patients from the Secondary Prevention of Small Subcortical Strokes (SPS3) trial with a baseline cognitive exam administered in English by certified SPS3 personnel, 14-180 days after qualifying lacunar stroke. We considered a baseline score of ≤86 on the Cognitive Assessment Screening Instrument to indicate global cognitive impairment, <10 on the Clock Drawing on Command test to indicate executive function impairment, and domain-specific summary scores in the lowest quartile to indicate memory and nonmemory impairment. We used Cox proportional hazards models to estimate the association between poststroke cognitive impairment and subsequent risk of recurrent stroke and death. RESULTS: The study included 1,528 participants with a median enrollment time of 62 days after qualifying stroke. During a mean follow-up of 3.9 years, 11.4% of participants had recurrent stroke and 8.2% died. In the fully adjusted models, memory impairment was independently associated with an increased risk of recurrent stroke (hazard ratio, 1.48; 95% confidence interval [95% CI]: 1.04-2.09) and death (hazard ratio, 1.87; 95% CI: 1.25-2.79). Global impairment (hazard ratio, 1.66; 95% CI: 1.06-2.59) and nonmemory impairment (hazard ratio, 1.74; 95% CI: 1.14-2.67) were associated with an increased risk of death. DISCUSSION/CONCLUSION: After lacunar stroke, memory impairment was an independent predictor of recurrent stroke and death, while global and nonmemory impairment were associated with death. Cognitive screening in lacunar stroke may help identify populations at higher risk of recurrent stroke and death.

Association of Lifetime TBI and Military Employment with Late Life ADL Functioning: A Population-Based Prospective Cohort Study.

OBJECTIVE: To determine associations of traumatic brain injury (TBI) and military employment with activities of daily living (ADL) in late life. DESIGN: Population-based prospective cohort study with biennial follow-up and censoring at the time of dementia diagnosis. SETTING: Community-based integrated health care delivery system. PARTICIPANTS: Participants (N=4953) were men (n=2066) and women (n=2887) aged ≥65 years who were dementia free. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: ADL difficulties at baseline and accumulation during follow-up. RESULTS: TBI with loss of consciousness (LOC) before the age of 40 years was associated with slightly higher ADL difficulty at baseline for women (rate ratio [RR], 1.44; 95% confidence interval [CI], 1.08-1.93; P=.01). For men, TBI with LOC at any age was associated with greater ADL difficulty at baseline (age <40y: RR, 1.58; 95% CI, 1.20-2.08; P=.001; age ≥40y: RR, 2.14; 95% CI, 1.24-3.68; P=.006). TBI with LOC was not associated with the rate of accumulation of ADL difficulties over time in men or women. There was no evidence of an association between military employment and either outcome, nor of an interaction between military employment and TBI with LOC. Findings were consistent across a variety of sensitivity analyses. CONCLUSIONS: Further investigation into factors underlying greater late life functional impairment among survivors of TBI is warranted.

Hearing impairment and missing cognitive test scores in a population-based study of older adults: The Atherosclerosis Risk in Communities neurocognitive study.

INTRODUCTION: Hearing impairment is associated with poor cognitive test performance in older adults. However, hearing's impact on cognitive test completion is poorly described, and missing cognitive data due to hearing impairment could misestimate the association. METHODS: We investigated if hearing impairment is associated with missing neurocognitive scores in 3678 adults (72-94 years). Hearing impairment was defined by the better-ear pure tone average of speech-frequency thresholds (0.5-4 kHz) >25 decibels. RESULTS: Hearing impairment was associated with greater missingness on all auditory-only tests, including Logical Memory (prevalence ratio [PR] comparing ≥ moderate impairment vs normal hearing:1.68, 95% confidence interval [CI] 1.26, 2.25) and Digits Backwards (PR 1.62; 95% CI 1.21, 2.17); and two non-auditory tests, Boston Naming (PR 1.61; 95% CI 1.21, 2.17) and Trail Making B (PR 1.55; 95% CI 1.29, 1.86). Models that imputed missing cognitive scores showed the strongest hearing-cognition associations. DISCUSSION: Older adults with hearing impairment are less likely to complete cognitive testing, thereby underestimating the hearing impairment-cognition relationship.

Generalizability of findings from a clinical sample to a community-based sample: A comparison of ADNI and ARIC.

INTRODUCTION: Clinic-based study samples, including the Alzheimer's Disease Neuroimaging Initiative (ADNI), offer rich data, but findings may not generalize to community-based settings. We compared associations in ADNI to those in the Atherosclerosis Risk in Communities (ARIC) study to assess generalizability across the two settings. METHODS: We estimated cohort-specific associations among risk factors, cognitive test scores, and neuroimaging outcomes to identify and quantify the extent of significant and substantively meaningful differences in associations between cohorts. We explored whether using more homogenous samples improved comparability in effect estimates. RESULTS: The proportion of associations that differed significantly between cohorts ranged from 27% to 34% across sample subsets. Many differences were substantively meaningful (e.g., odds ratios [OR] for apolipoprotein E ε4 on amyloid positivity in ARIC: OR = 2.8, in ADNI: OR = 8.6). DISCUSSION: A higher proportion of associations differed significantly and substantively than would be expected by chance. Findings in clinical samples should be confirmed in more representative samples.

Association of mid-life serum lipid levels with late-life brain volumes: The atherosclerosis risk in communities neurocognitive study (ARICNCS).

BACKGROUND: Limited information exists regarding the association between midlife lipid levels and late-life total and regional brain volumes. METHODS: We studied 1872 participants in the longitudinal community-based Atherosclerosis Risk in Communities Neurocognitive Study. Serum lipid levels were measured in 1987-1989 (mean age, 53 ± 5 years). Participants underwent 3T brain MRI scans in 2011-2013. Brain volumes were measured using FreeSurfer image analysis software. Linear regression models were used to assess the associations between serum lipids and brain volumes modeled in standard deviation (SD) units, adjusting for potential confounders. RESULTS: In adjusted analyses, one SD higher low-density lipoprotein cholesterol (LDL) levels were associated with larger total brain volumes (ß 0.033, 95% CI 0.006-0.060) as well as larger volumes of the temporal (ß 0.038, 95% CI 0.003-0.074) and parietal lobes (ß 0.044, 95% CI 0.009-0.07) and Alzheimer disease-related region (ß 0.048, 95% CI 0.048-0.085). Higher triglyceride levels were associated with smaller total brain volumes (ß -0.033, 95% CI -0.060, -0.007). The associations between LDL levels and brain volumes were modified by age (P for interaction <0.001), with higher LDL levels associated with larger total and regional brain volumes only among adults >53 years at baseline, and were attenuated after application of weights to account for informative attrition, although associations with the parietal and Alzheimer's disease-related region remained significant. High-density lipoprotein cholesterol was not associated with brain volumes. CONCLUSION: Higher LDL levels in late midlife were associated with larger brain volumes later in life, while higher triglyceride levels were associated with smaller brain volumes. These associations were driven by adults >53 years at baseline.

Development of Algorithmic Dementia Ascertainment for Racial/Ethnic Disparities Research in the US Health and Retirement Study.

BACKGROUND: Disparities research in dementia is limited by lack of large, diverse, and representative samples with systematic dementia ascertainment. Algorithmic diagnosis of dementia offers a cost-effective alternate approach. Prior work in the nationally representative Health and Retirement Study has demonstrated that existing algorithms are ill-suited for racial/ethnic disparities work given differences in sensitivity and specificity by race/ethnicity. METHODS: We implemented traditional and machine learning methods to identify an improved algorithm that: (1) had ≤5 percentage point difference in sensitivity and specificity across racial/ethnic groups; (2) achieved ≥80% overall accuracy across racial/ethnic groups; and (3) achieved ≥75% sensitivity and ≥90% specificity overall. Final recommendations were based on robustness, accuracy of estimated race/ethnicity-specific prevalence and prevalence ratios compared to those using in-person diagnoses, and ease of use. RESULTS: We identified six algorithms that met our prespecified criteria. Our three recommended algorithms achieved ≤3 percentage point difference in sensitivity and ≤5 percentage point difference in specificity across racial/ethnic groups, as well as 77%-83% sensitivity, 92%-94% specificity, and 90%-92% accuracy overall in analyses designed to emulate out-of-sample performance. Pairwise prevalence ratios between non-Hispanic whites, non-Hispanic blacks, and Hispanics estimated by application of these algorithms are within 1%-10% of prevalence ratios estimated based on in-person diagnoses. CONCLUSIONS: We believe these algorithms will be of immense value to dementia researchers interested in racial/ethnic disparities. Our process can be replicated to allow minimally biasing algorithmic classification of dementia for other purposes.