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Background and Objectives:Exposure to socioeconomic disadvantage is associated with early-onset cognitive aging. Biological aging, the progressive loss of system integrity that occurs as we age is proposed as a modifiable process mediating this health inequality. We examined whether socioeconomic disparities in cognitive aging in mid-to late-life adults is explained by accelerated biological aging similarly across race, ethnicity and sex/gender.Methods:Data was from a prospective cohort study of the U.S. Health and Retirement Study DNA-methylation sub-study. Socioeconomic status (SES) was measured from years of education and household wealth at baseline. The extent and pace of biological aging were quantified using three DNA-methylation measures: PhenoAge, GrimAge, and DunedinPoAm. Cognitive aging was measured from repeated longitudinal assessments of immediate and delayed word recall. Latent growth curve modeling estimated participants’ level of memory performance and rate of decline over 2-11 follow-up assessments spanning 2-20 years. Multiple-group models were estimated to assess whether the relationship between SES and memory trajectories was mediated by biological aging across racial-ethnic by sex/gender subgroups.Results:Data from a total of 3,997 adults aged 50-100 were analyzed. Participants with lower SES had lower memory performance, faster decline and exhibited accelerated biological aging (SES effect size associations (β) ranged from .08 to .41). Accelerated biological aging was associated with decreased memory performance and faster memory decline (effect-size range .03 to .23). SES-biological aging associations were strongest for White men and women and weakest for Latinx women. The relationship between biological aging measures and memory was weaker for Black participants compared with White and Latinx people. In mediation analysis, biological aging accounted for 4-27% of the SES-memory gradient in White participants. There was little evidence of mediation in Black or Latinx participants.Discussion:Among a national sample of mid-to late-life adults, DNA-methylation measures of biological aging were variably associated with memory trajectories and SES across White, Black, and Latinx mid-to late-life adults. These results challenge the assumption that DNA-methylation biomarkers of aging that were developed in primarily White people can equivalently quantify aging processes affecting cognition in Black and Latinx mid-to late-life adults.

Background and ObjectivesTo investigate sociodemographic and medical predictors of incident mild cognitive impairment (MCI) and subsequent course of MCI at follow-up, including sustained MCI diagnosis, classification as cognitively normal, and progression to dementia.MethodsWithin a community-based cohort, diagnoses of MCI were made with a published algorithm. Diagnosis of dementia was based on clinical consensus. Cox regressions estimated hazard ratios of incident MCI associated with several predictors. Modified Poisson regressions estimated relative risks associated with predictors of diagnostic status at follow-up after incidence.ResultsAmong 2,903 cognitively normal participants at baseline, 752 developed MCI over an average of 6.3 (SD 4.5) years (incidence rate 56 per 1,000 person-years). Presence of APOE ε4 and higher medical burden increased risk of incident MCI, while more years of education, more leisure activities, and higher income decreased this risk. Of the incident MCI cases, after an average of 2.4 years of follow-up, 12.9% progressed to dementia, 9.6% declined in functioning and did not meet the algorithmic criteria for MCI but did not meet the clinical criteria for dementia, 29.6% continued to meet MCI criteria, and 47.9% no longer met MCI criteria. Multidomain MCI, presence of APOE ε4, depressive symptoms, and antidepressant use increased the risk of progression to dementia.DiscussionThis community-based study showed that almost half of the individuals with incident MCI diagnoses were classified as cognitively normal at follow-up. Predictors of incident MCI demonstrably differed from those of subsequent MCI course; these findings can refine expectations for cognitive and functional course of those presenting with MCI.

BackgroundHigher education consistently predicts improved late-life cognition. Racial differences in educational attainment likely contribute to inequities in dementia risk. However, few studies of education and cognition have controlled for prospectively measured early-life confounders or evaluated whether the education late-life cognition association is modified by race/ethnicity.MethodsAmong 2343 Black and White Project Talent Aging Study participants who completed telephone cognitive assessments, we evaluated whether the association between years of education and cognition (verbal fluency, memory/recall, attention, and a composite cognitive measure) differed by race, and whether these differences persisted when adjusting for childhood factors, including the cognitive ability.ResultsIn fully adjusted linear regression models, each additional year of education was associated with higher composite cognitive scores for Black [β=0.137; 95% confidence interval (CI)=0.068, 0.206] and White respondents (β=0.056; CI=0.034, 0.078) with an interaction with race ( P =0.03). Associations between education and memory/recall among Black adults (β=0.036; CI=-0.037, 0.109) and attention among White adults (β=0.022; CI=-0.002, 0.046) were nonsignificant. However, there were significant race-education interactions for the composite ( P =0.03) and attention measures ( P

https://pubmed.ncbi.nlm.nih.gov/34662699/, White matter hyperintensities (WMH) are areas of increased signal visualized on T2-weighted fluid attenuated inversion recovery (FLAIR) brain magnetic resonance imaging (MRI) sequences. They are typically attributed to small vessel cerebrovascular disease in the context of aging. Among older adults, WMH are associated with risk of cognitive decline and dementia, stroke, and various other health outcomes. There has been increasing interest in incorporating quantitative WMH measurement as outcomes in clinical trials, observational research, and clinical settings. Here, we present a novel, fully automated, unsupervised detection algorithm for WMH segmentation and quantification. The algorithm uses a robust preprocessing pipeline, including brain extraction and a sample-specific mask that incorporates spatial information for automatic false positive reduction, and a half Gaussian mixture model (HGMM). The method was evaluated in 24 participants with varying degrees of WMH (4.9-78.6 cm3) from a community-based study of aging and dementia with dice coefficient, sensitivity, specificity, correlation, and bias relative to the ground truth manual segmentation approach performed by two expert raters. Results were compared with those derived from commonly used available WMH segmentation packages, including SPM lesion probability algorithm (LPA), SPM lesion growing algorithm (LGA), and Brain Intensity AbNormality Classification Algorithm (BIANCA). The HGMM algorithm derived WMH values that had a dice score of 0.87, sensitivity of 0.89, and specificity of 0.99 compared to ground truth. White matter hyperintensity volumes derived with HGMM were strongly correlated with ground truth values (r = 0.97, p = 3.9e-16), with no observable bias (-1.1 [-2.6, 0.44], p-value = 0.16). Our novel algorithm uniquely uses a robust preprocessing pipeline and a half-Gaussian mixture model to segment WMH with high agreement with ground truth for large scale studies of brain aging.

Systemic racism leads to racial/ethnic residential segregation, which can result in health inequities. We examined if the associations between residential segregation and later-life cognition and dementia differed based on segregation measure and by participant race/ethnicity. Tests of memory (n = 4616), language (n = 4333), visuospatial abilities (n = 4557), and incident dementia (n = 4556) were analyzed in older residents of Northern Manhattan, New York (mean age: 75.7 years). Segregation was measured at the block group-level using three indices: dissimilarity, isolation, and interaction. We fit multilevel linear or Cox proportional hazards models and included a race/ethnicity × segregation term to test for differential associations, adjusting for socioeconomic and health factors. Living in block groups with higher proportions of minoritized people was associated with −0.05 SD lower language scores. Living in block groups with higher potential contact between racial/ethnic groups was associated with 0.06–0.1 SD higher language scores. The findings were less pronounced for other cognitive domains and for incident dementia. Non-Hispanic Black adults were most likely to experience negative effects of neighborhood segregation on cognition (language and memory) and dementia. All indices partly capture downstream effects of structural racism (i.e., unequal distributions of wealth/resources) on cognition. Therefore, desegregation and equitable access to resources have the potential to improve later-life cognitive health.

ObjectivesMyocyte Enhancer Factor 2C (MEF2C) is identified as a candidate gene contributing to the risk of developing Alzheimer’s disease. However, little is known about whether MEF2C plays a role in specific aspects of cognition among older adults. The current study investigated the association of common variants in the MEF2C gene with four cognitive domains including memory, visuospatial functioning, processing speed and language among non-demented individuals.MethodParticipants from two ethnic groups, Non-Hispanic White (NHW; n = 537) and Caribbean Hispanic (CH; n = 1,197) from the Washington Heights-Inwood Community Aging Project (WHICAP) study, were included. Genetic association analyses using WHICAP imputed genome-wide data (GWAS) were conducted for the various cognition domains.ResultsSingle nucleotide polymorphisms (SNP) variants in the MEF2C gene showed nominally significant associations in all cognitive domains but for different SNPs across both the ethnic groups. In NHW participants, the strongest associations were present for memory (rs302484), language (rs619584), processing speed (rs13159808), and visuospatial functioning (several SNPs). In CH, strongest associations were observed for memory (rs34822815), processing speed (rs304141), visuospatial functioning (rs10066711 and rs10038371), and language (rs304153).DiscussionMEF2C variant-cognitive associations shed light on an apparent role for MEF2C in both memory and non-memory aspects of cognition in individuals from NHW and CH ancestries. However, the little overlap in the specific SNP-cognition associations in CH versus NHW highlights the differences in genetic architectural variations among those from different ancestries that should be considered while studying the MEF2C gene.

Hypertension is an established risk factor for cognitive decline and dementia in older adults, highlighting the potential importance of antihypertensive treatments in prevention efforts. Work surrounding antihypertensive treatments has suggested possible salutary effects on cognition and neuropathology. Several studies have specifically highlighted renin-angiotensin system drugs, including AT1-receptor blockers and angiotensin-converting-enzyme inhibitors, as potentially benefiting cognition in later life. A small number of studies have further suggested renin-angiotensin system drugs that cross the blood-brain barrier may be linked to lower dementia risk compared to their non-penetrant counterparts. The present meta-analysis sought to evaluate the potential cognitive benefits of blood-brain barrier crossing renin-angiotensin system drugs relative to their non-penetrant counterparts. We harmonized longitudinal participant data from 14 cohorts from 6 countries (Australia, Canada, Germany, Ireland, Japan, United States), for a total of 12,849 individuals at baseline, and assessed for blood-brain barrier crossing potential within antihypertensive medications used by cognitively normal participants. We analyzed seven cognitive domains (attention, executive function, language, verbal memory learning, recall, mental status, and processing speed) using analysis of covariance (adjusted for age, sex, and education) and meta-analyses. Older adults taking blood-brain barrier-crossing renin-angiotensin drugs exhibited better memory recall over up to 3 years of follow-up, relative to those taking non-penetrant medications, despite their relatively higher vascular risk burden. Conversely, those taking non-blood-brain barrier-penetrant medications showed better attention over the same follow-up period, although their lower vascular risk burden may partially explain this result. Findings suggest links between blood-brain barrier crossing renin-angiotensin drugs and less memory decline.

ObjectiveAlzheimer disease (AD) is a common and costly neurodegenerative disorder. A large proportion of AD risk is heritable, and many genetic risk factors have been identified. The objective of this study was to test the hypothesis that cumulative genetic risk of known AD markers contributed to odds of dementia in a population-based sample.MethodsIn the US population-based Health and Retirement Study (waves 1995–2014), we evaluated the role of cumulative genetic risk of AD, with and without the APOE ε4 alleles, on dementia status (dementia, cognitive impairment without dementia, borderline cognitive impairment without dementia, and cognitively normal). We used logistic regression, accounting for demographic covariates and genetic principal components, and analyses were stratified by European and African genetic ancestry.ResultsIn the European ancestry sample (n = 8,399), both AD polygenic score excluding the APOE genetic region (odds ratio [OR] = 1.10; 95% confidence interval [CI]: 1.00–1.20) and the presence of any APOE ε4 alleles (OR = 2.42; 95% CI: 1.99–2.95) were associated with the odds of dementia relative to normal cognition in a mutually adjusted model. In the African ancestry sample (n = 1,605), the presence of any APOE ε4 alleles was associated with 1.77 (95% CI: 1.20–2.61) times higher odds of dementia, whereas the AD polygenic score excluding the APOE genetic region was not significantly associated with the odds of dementia relative to normal cognition 1.06 (95% CI: 0.97–1.30).ConclusionsCumulative genetic risk of AD and APOE ε4 are both independent predictors of dementia in European ancestry. This study provides important insight into the polygenic nature of dementia and demonstrates the utility of polygenic scores in dementia research.

The association between sex/gender and aging-related cognitive decline remains poorly understood because of inconsistencies in findings. Such heterogeneity could be attributable to the cognitive functions studied and study population characteristics, but also to differential selection by dropout and death between men and women. We aimed to evaluate the impact of selection by dropout and death on the association between sex/gender and cognitive decline. We first compared the statistical methods most frequently used for longitudinal data, targeting either population estimands (marginal models fitted by generalized estimating equations) or subject-specific estimands (mixed/joint models fitted by likelihood maximization) in 8 studies of aging: 6 population-based studies (the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) Study (1996–2009), Personnes Âgées QUID (PAQUID; 1988–2014), the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study (2003–2016), the Three-City Study (Bordeaux only; 1999–2016), the Washington Heights-Inwood Community Aging Project (WHICAP; 1992–2017), and the Whitehall II Study (2007–2016)) and 2 clinic-based studies (the Alzheimer’s Disease Neuroimaging Initiative (ADNI; 2004–2017) and a nationwide French cohort study, MEMENTO (2011–2016)). We illustrate differences in the estimands of the association between sex/gender and cognitive decline in selected examples and highlight the critical role of differential selection by dropout and death. Using the same estimand, we then contrast the sex/gender–cognitive decline associations across cohorts and cognitive measures suggesting a residual differential sex/gender association depending on the targeted cognitive measure (memory or animal fluency) and the initial cohort selection. We recommend focusing on subject-specific estimands in the living population for assessing sex/gender differences while handling differential selection over time.

Introduction Low vitamin D intake and low vitamin D circulating levels have been associated with increased risk for dementia. We aimed to examine the association between vitamin D intake and dementia in a multiethnic cohort. Methods A longitudinal study of 1759 non-demented older (≥65 years) participants of the Washington Heights-Inwood Columbia Aging Project with follow-up visits and completed a food frequency questionnaire. Dementia was diagnosed by consensus using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Cox hazard regression was performed. Results During a mean follow-up of 5.8 years, 329 participants developed dementia. Participants with the highest tertile of vitamin D intake from food sources had decreased risk (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.54-0.97, P = .030) for dementia compared with those with the lowest tertile, adjusting for age, sex, race/ethnicity, education, apolipoprotein E (APOE)-e4, physical activity, Mediterranean diet (MeDI) score, income, depression, hypertension, diabetes, cardiovascular disease, and smoking. Discussion Higher vitamin D intake is associated with decreased risk of dementia in a multiethnic cohort.

Objectives:Previous cross-sectional studies have documented associations between positive psychosocial factors, such as self-efficacy and emotional support, and late-life cognition. Further, the magnitudes of concurrent associations may differ across racial and ethnic groups that differ in Alzheimer’s disease risk. The goals of this longitudinal study were to characterize prospective associations between positive psychosocial factors and cognitive decline and explicitly test for differential impact across race and ethnicity.Methods:578 older adults (42% non-Hispanic Black, 31% non-Hispanic White, and 28% Hispanic) in the Washington Heights-Inwood Columbia Aging Project completed cognitive and psychosocial measures from the NIH Toolbox and standard neuropsychological tests over 2.4 years. Latent difference scores were used to model associations between positive psychosocial factors and cognitive decline controlling for baseline cognition, sociodemographics, depressive symptoms, physical health, and other positive psychosocial factors. Multiple-group modeling was used to test interactions between the positive psychosocial factors and race/ethnicity.Results:Higher NIH Toolbox Friendship scores predicted less episodic memory decline. One standard deviation increase in friendship corresponded to 6 fewer years of memory aging. This association did not significantly differ across racial/ethnic groups.Conclusions:This longitudinal study provides support for the potential importance of friendships for subsequent episodic memory trajectories among older adults from three ethnic groups. Further study into culturally informed interventions is needed to investigate whether and how friend networks may be targeted to promote cognitive health in late life.

The Washington University School of Medicine Knight Alzheimer Disease Research Center's "African American Participation in Alzheimer Disease Research: Effective Strategies" Workshop convened to address a major limitation of the ongoing scientific progress regarding Alzheimer's disease and related dementias (ADRD): participants in most ADRD research programs overwhelmingly have been limited to non-Hispanic white persons, thus precluding knowledge as to how ADRD may be represented in non-white individuals. Factors that may contribute to successful recruitment and retention of African Americans into ADRD research were discussed and organized into actionable next steps as described within this report.

Objective The genetic bases of Alzheimer's disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra‐rare variants in Alzheimer's disease, using whole‐exome sequencing in 20,197 individuals. Methods We used a gene‐based collapsing analysis of loss‐of‐function ultra‐rare variants in a case–control study design with data from the Washington Heights‐Inwood Columbia Aging Project, the Alzheimer's Disease Sequencing Project and unrelated individuals from the Institute of Genomic Medicine at Columbia University. Results We identified 19 cases carrying extremely rare SORL1 loss‐of‐function variants among a collection of 6,965 cases and a single loss‐of‐function variant among 13,252 controls (P = 2.17 × 10−8; OR: 36.2 [95% CI: 5.8–1493.0]). Age‐at‐onset was 7 years earlier for patients with SORL1 qualifying variant compared with noncarriers. No other gene attained a study‐wide level of statistical significance, but multiple top‐ranked genes, including GRID2IP,WDR76 and GRN, were among candidates for follow‐up studies. Interpretation This study implicates ultra‐rare, loss‐of‐function variants in SORL1 as a significant genetic risk factor for Alzheimer's disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimer's disease cases and controls. This is the first investigation to establish a genome‐wide statistically significant association between multiple extremely rare loss‐of‐function variants in SORL1 and Alzheimer's disease in a large whole‐exome study of unrelated cases and controls.

Objective:Hispanics/Latinos are the largest and fastest-growing minority population in the United States. To facilitate appropriate outcome assessment of this expanding population, the NIH Toolbox for Assessment of Neurological and Behavioral Function® (NIH Toolbox®) was developed with particular attention paid to the cultural and linguistic needs of English- and Spanish-speaking Hispanics/Latinos.Methods:A Cultural Working Group ensured that all included measures were appropriate for use with Hispanics/Latinos in both English and Spanish. In addition, a Spanish Language Working Group assessed all English-language NIH Toolbox measures for translatability.Results:Measures were translated following the Functional Assessment of Chronic Illness Therapy (FACIT) translation methodology for instances where language interpretation could impact scores, or a modified version thereof for more simplified translations. The Spanish versions of the NIH Toolbox Cognition Battery language measures (i.e., Picture Vocabulary Test, Oral Reading Recognition Test) were developed independently of their English counterparts.Conclusions:The Spanish-language version of the NIH Toolbox provides a much-needed set of tools that can be selected as appropriate to complement existing protocols being conducted with the growing Hispanic/Latino population in the United States.

INTRODUCTIONAlzheimer’s disease (AD) is a common and costly neurodegenerative disorder. A large proportion of risk is heritable and many genetic risk factors for AD have been identified. The cumulative genetic risk of known markers has not been benchmarked for dementia in a population-based sample.METHODSIn the United States population-based Health and Retirement Study (HRS) (waves 1995-2014), we evaluated the role of cumulative genetic risk for AD, with and without the APOE-ε4 alleles, on dementia status (dementia, cognitive impairment without dementia, borderline cognitive impairment without dementia, cognitively normal). We used logistic regression, accounting for demographic covariates and genetic principal components, and analyses were stratified by European and African genetic ancestry.RESULTSIn the European ancestry sample (n=8399), both AD polygenic score excluding the APOE genetic region (odds ratio (OR)=1.10; 95% confidence interval (CI): 1.00, 1.20) and the presence of any APOE-ε4 alleles (OR=2.42; 95% CI: 1.99, 2.95) were associated with the odds of dementia relative to normal cognition in a mutually-adjusted model. In the African ancestry sample (n=1605), the presence of any APOE-ε4 alleles was associated with 1.77 (95% CI: 1.20, 2.61) times higher odds of dementia, while the AD polygenic score excluding the APOE genetic region was not significantly associated with the odds of dementia relative to normal cognition 1.06 (95% CI: 0.97, 1.30).DISCUSSIONCumulative genetic risk for AD and APOE-ε4 are both independent predictors of dementia. This study provides important insight into the polygenic nature of dementia and demonstrates the utility of polygenic scores in dementia research.

Background: There is mounting evidence that long-term exposure to air pollution is related to accelerated cognitive decline in aging populations. Factors that influence individual susceptibility remain largely unknown, but may involve the apolipoprotein E genotype E4 (APOE-ε4) allele. Objectives: We assessed whether the association between long-term exposure to ambient air pollution and cognitive decline differed by APOE-ε4 status and cognitive risk factors. Methods: The Washington Heights Inwood Community Aging Project (WHICAP) is a prospective study of aging and dementia. Neuropsychological testing and medical examinations occur every 18–24 months. We used mixed-effects models to evaluate whether the association between markers of ambient air pollution (nitrogen dioxide [NO2]), fine [PM2.5], and coarse [PM10] particulate matter) and the rate of decline in global and domain-specific cognition differed across strata defined by APOE-ε4 genotypes and cognitive risk factors, adjusting for sociodemographic factors and temporal trends. Results: Among 4821 participants with an average of 6 years follow-up, higher concentrations of ambient air pollution were associated with more rapid cognitive decline. This association was more pronounced among APOE-ε4 carriers (p

Introduction We investigated metabolites in plasma to capture systemic biochemical changes associated with Alzheimer's disease (AD). Methods Metabolites in plasma were measured in 59 AD cases and 60 healthy participants of African American (AA), Caribbean Hispanic (CH), and non‐Hispanic white (NHW) ancestry using untargeted liquid‐chromatography–based ultra‐high‐resolution mass spectrometry. Metabolite differences between AD and healthy, ethnic groups and apolipoprotein E gene (APOE) ε4 status were analyzed. Untargeted network analysis identified pathways enriched in AD‐associated metabolites. Results A total of 5929 annotated metabolites were measured. Partial least squares discriminant analysis (PLS‐DA) inferred that AD clustered separately from healthy controls (area under the curve [AUC] = 0.9816); discriminating pathways included glycerophospholipid, sphingolipid, and non‐essential amino acid (alanine, aspartate, glutamate) metabolism. Metabolic features in AA clustered differently from CH and NHW (AUC = 0.9275), and differed between APOE ε4 carriers and non‐carriers (AUC = 0.9972). Discussion Metabolites, specifically lipids, were associated with AD, APOE ε4, and ethnic group. Metabolite profiling can identify perturbed AD pathways, but genetic and ancestral background need to be considered.

Introduction: The Harmonized Cognitive Assessment Protocol (HCAP) Project is a substudy within the Health and Retirement Study (HRS), an ongoing nationally representative panel study of about 20,000 adults aged 51 or older in the United States. The HCAP is part of an international research collaboration funded by the National Institute on Aging to better measure and identify cognitive impairment and dementia in representative population-based samples of older adults, in the context of ongoing longitudinal studies of aging in high-, middle-, and low-income countries around the world. Methods: The HCAP cognitive test battery was designed to measure a range of key cognitive domains affected by cognitive aging (including attention, memory, executive function, language, and visuospatial function) and to allow harmonization and comparisons to other studies in the United States and around the world. The HCAP included a pair of in-person interviews, one with the target HRS respondent (a randomly selected HRS sample member, aged 65+) that lasted approximately 1 h and one with an informant nominated by the respondent that lasted approximately 20 min. The final HRS HCAP sample included 3,496 study subjects, representing a 79% response rate among those invited to participate. Conclusion: Linking detailed HCAP cognitive assessments to the wealth of available longitudinal HRS data on cognition, health, biomarkers, genetics, health care utilization, informal care, and economic resources and behavior will provide unique and expanded opportunities to study cognitive impairment and dementia in a nationally representative US population-based sample. The fielding of similar HCAP projects in multiple countries around the world will provide additional opportunities to study international differences in the prevalence, incidence, and outcomes of dementia globally with comparable data. Like all HRS data, HCAP data are publicly available at no cost to researchers.

BackgroundImputation has become a standard approach in genome-wide association studies (GWAS) to infer in silico untyped markers. Although feasibility for common variants imputation is well established, we aimed to assess rare and ultra-rare variants’ imputation in an admixed Caribbean Hispanic population (CH).MethodsWe evaluated imputation accuracy in CH (N = 1,000), focusing on rare (0.1% ≤minor allele frequency (MAF) ≤ 1%) and ultra-rare (MAF < 0.1%) variants. We used two reference panels, the Haplotype Reference Consortium (HRC; N = 27,165) and 1000 Genome Project (1000G phase 3; N = 2,504) and multiple phasing (SHAPEIT, Eagle2) and imputation algorithms (IMPUTE2, MACH-Admix). To assess imputation quality, we reported: a) high-quality variant counts according to imputation tools’ internal indexes (e.g. IMPUTE2 “Info”≥80%). b) Wilcoxon Signed-Rank Test comparing imputation quality for genotyped variants that were masked and imputed; c) Cohen’s kappa coefficient to test agreement between imputed and whole-exome sequencing (WES) variants; d) imputation of G206A mutation in the PSEN1 (ultra-rare in the general population an more frequent in CH) followed by confirmation genotyping. We also tested ancestry proportion (European, African and Native American) against WES-imputation mismatches in a Poisson regression fashion.ResultsSHAPEIT2 retrieved higher percentage of imputed high-quality variants than Eagle2 (rare: 51.02% vs. 48.60%; ultra-rare 0.66% vs 0.65%, Wilcoxon p-value < 0.001). SHAPEIT-IMPUTE2 employing HRC outperformed 1000G (64.50% vs. 59.17%; 1.69% vs 0.75% for high-quality rare and ultra-rare variants, respectively; Wilcoxon p-value < 0.001). SHAPEIT-IMPUTE2 outperformed MaCH-Admix. Compared to 1000G, HRC-imputation retrieved a higher number of high-quality rare and ultra-rare variants, despite showing lower agreement between imputed and WES variants (e.g. rare: 98.86% for HRC vs. 99.02% for 1000G). High Kappa (K = 0.99) was observed for both reference panels. Twelve G206A mutation carriers were imputed and all validated by confirmation genotyping. African ancestry was associated with higher imputation errors for uncommon and rare variants (p-value < 1e-05).ConclusionReference panels with larger numbers of haplotypes can improve imputation quality for rare and ultra-rare variants in admixed populations such as CH. Ethnic composition is an important predictor of imputation accuracy, with higher African ancestry associated with poorer imputation accuracy.

Risk of dementia is both racially and spatially patterned. Less is known about sex/gender differences in pathways linking birth place to late-life cognitive outcomes in older non-Latino Blacks. The 1464 Black men and women included in these analyses were Northern Manhattan residents. Cox regressions revealed that Stroke-Belt South (SB) and Non-Stroke-Belt South (NSB) birth was associated with a higher dementia risk, adjusted for birth year, childhood SES, and risk of death. Compared to Northern-born (NB) men, SB men had the highest risk, followed by NSB women and SB women, while NSB men and NB women had a similar risk to NB men. The higher risk for SB men and NSB women remained after adjusting for education, adult income, and CVD burden. Future work should identify why birth in the SB is uniquely detrimental for cognitive health among Black men, while birth in NSB has the strongest impact on Black women.

The REGARDS study enrolled 30,239 whites and blacks aged >45 from 2003 – 2007, with oversampling of blacks and residents of the Stroke Belt. Potential participants were mailed a letter/brochure followed by telephone call. After verbal consent, telephone interview assessed cardiovascular health and cognitive function. In a home visit, measurements of risk factors, biological samples, EKG, written consent were obtained; during the in-home visit, self-administrated questionnaires were left to be completed and returned. Participants are followed for hospitalizations via telephone at 6-month intervals. Annually and biennially, brief and more comprehensive assessments of global cognitive function are conducted. Medical records for suspected strokes are collected with adjudication by stroke experts. A 2nd in-home and telephone assessment was conducted 2013-2016, approximately 10 years after baseline. This presentation will describe the methodological details of REGARDS, progress on the specific aims of the current grant, and establish the context for the remaining presentations.

Examining the neural correlates underlying racial differences in cognitive functioning is necessary to help clarify mechanisms and to improve the generalizability of findings related to brain-behavior relationships. This systematic review aimed to determine whether there are racial differences in structural markers of brain aging among community-dwelling, neurologically healthy adults aged 18 and older. We identified studies (n=5,399) from searches in Ovid Medline, Ovid PsychINFO, and Elsevier EMBASE published until February 13, 2020. We included original articles that examined structural markers of brain aging and neuropathology across individuals from more than one race or ethnicity. These measures included magnetic resonance imaging, positron emission tomography amyloid and tau, cerebrospinal fluid amyloid, tau, and neurofilament light chain and computed tomography. Two reviewers independently screened full-text articles. We will present ongoing results and discuss the current state of knowledge, quality of existing studies, and gaps in the literature and highlight potentially key next steps.

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, "Una manera de hacer Europa", La "Marató TV3" grant (20141210 to J.F.) Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.

We used differences in state school policies as natural experiments to evaluate the joint influence of educational quantity and quality on late-life physical and mental health. Using US Census microsample data, historical measures of state compulsory schooling and school quality (term length, student-teacher ratio, and attendance rates) were combined via regression modeling on a scale corresponding to years of education (policy-predicted years of education (PPYEd)). PPYEd values were linked to individual-level records for 8,920 black and 14,605 white participants aged ≥45 years in the Reasons for Geographic and Racial Differences in Stroke study (2003–2007). Linear and quantile regression models estimated the association between PPYEd and Physical Component Summary (PCS) and Mental Component Summary (MCS) from the Short Form Health Survey. We examined interactions by race and adjusted for sex, birth year, state of residence at age 6 years, and year of study enrollment. Higher PPYEd was associated with better median PCS (β = 1.28, 95% confidence interval (CI): 0.40, 1.49) and possibly better median MCS (β = 0.46, 95% CI: –0.01, 0.94). Effect estimates were higher among black (vs. white) persons (PCS × race interaction, β = 0.22, 95% CI: –0.62, 1.05, and MCS × race interaction, β = 0.18; 95% CI: –0.08, 0.44). When incorporating both school quality and duration, this quasiexperimental analysis found mixed evidence for a causal effect of education on health decades later.

Social engagement has been linked to preserved cognitive functioning in later life. While social engagement is often operationalized as network size, networks can also vary in composition. In addition, social resources may differentially affect cognition in minority groups at higher risk of cognitive impairment. This study examined relationships between network characteristics and cognition in the ethnically and racially diverse Washington Heights-Inwood Columbia Aging Project (n= 548, 60–93). Multiple regressions revealed that friend-focused networks were associated with better memory and language than family-focused networks. This finding may reflect the cognitive benefits of greater adaptive social pruning and lower homophily, which have both been found to characterize friend-focused networks, but direct tests are needed. Larger network size was only associated with better memory within friend-focused networks. Stratified analyses revealed that effects were driven by African Americans, suggesting that social networks may play a vital role in cognitive aging in this group.”

Racial disparities in cognitive function are well-known. However, the role of neighborhood environments in modifying trajectories of cognitive function by race has not been examined using national data. Using data from 26,439 non-Hispanic Black and White Americans (mean age 64) in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study we used gender-stratified growth curve models to examine how baseline census tract neighborhood environments (socioeconomic disadvantage, affluence, racial/immigrant composition, public libraries, crime rates, and urbanicity (captured through population density)) were associated with trajectories of cognitive impairment (Six-item Screener (SIS) scores

Verbal fluency tasks are generally thought to be mediated by frontal brain regions for letter fluency and temporal regions for category fluency. This idea, however, is primarily based on lesion studies and adapted versions of the fluency tasks in functional neuroimaging, without fundamental evidence from structural neuroimaging in healthy individuals. We investigated the cortical structural correlates of letter and category fluency, including overlapping and different regions, in 505 individuals who participated in a community-based study of healthy aging. The correlation between cortical thickness and verbal fluency in whole-brain analyses revealed distinct cortical signatures for letter fluency, primarily in frontal regions, and category fluency, in frontal and temporal-parietal regions. There was a dissociation in the left inferior frontal gyrus between letter and category fluency, with increased thickness in the posterior-dorsal versus anterior-ventral parts, respectively. These results distinguish the detailed anatomical correlates for verbal fluency within the coarse frontal-temporal distinction inferred from lesion studies and among the mixture of regions identified in functional neuroimaging. The evidence for the anatomical substrates of letter and category fluency, each recruiting slightly different language and cognitive processes, can serve both clinical applications as well as a deeper theoretical understanding of the organization of the cerebral cortex.

White matter hyperintensities (WMHs) have been linked to cognitive dysfunction and dementia, although the reasons are unclear. One possibility is that WMHs promote neurodegeneration, which, in turn, affects cognition. We examined whether cortical thickness, a marker of neurodegeneration, mediates the relationship between WMHs and cognition among 519 older adults. Using conditional process analysis modeling techniques, we examined the association between WMH volume and global cognition and tested whether cortical thickness mediates this relationship statistically. We also tested specific regional hypotheses to determine whether cortical thickness or volume in the medial temporal lobe mediates the relationship between WMH volume and memory. Increased total WMH volume was associated with poorer global cognition and memory. The mediating effects were present across all cognitive domains. Global cortical thickness and medial temporal lobe thickness/volume mediated the relationship of WMH volume on global cognition and memory functioning. The mediating relationship was similar across racial and ethnic groups or across diagnostic groups (i.e., mild cognitive impairment/Alzheimer’s disease). The findings suggest that WMHs promote atrophy, which, in turn, drives cognitive decline and highlight a potential pathway in which small vessel cerebrovascular disease affects cognition by promoting neurodegenerative changes directly.

Objectives:The present study examined differences in neurocognitive outcomes among non-Hispanic Black and White stroke survivors using the NIH Toolbox-Cognition Battery (NIHTB-CB), and investigated the roles of healthcare variables in explaining racial differences in neurocognitive outcomes post-stroke.Methods:One-hundred seventy adults (91 Black; 79 White), who participated in a multisite study were included (age:M=56.4;SD=12.6; education:M=13.7;SD=2.5; 50% male; years post-stroke: 1–18; stroke type: 72% ischemic, 28% hemorrhagic). Neurocognitive function was assessed with the NIHTB-CB, using demographically corrected norms. Participants completed measures of socio-demographic characteristics, health literacy, and healthcare use and access. Stroke severity was assessed with the Modified Rankin Scale.Results:An independent samplesttest indicated Blacks showed more neurocognitive impairment (NIHTB-CB Fluid Composite T-score:M=37.63;SD=11.67) than Whites (Fluid T-score:M=42.59,SD=11.54;p=.006). This difference remained significant after adjusting for reading level (NIHTB-CB Oral Reading), and when stratified by stroke severity. Blacks also scored lower on health literacy, reported differences in insurance type, and reported decreased confidence in the doctors treating them. Multivariable models adjusting for reading level and injury severity showed that health literacy and insurance type were statistically significant predictors of the Fluid cognitive composite (pp=.02, respectively) and significantly mediated racial differences on neurocognitive impairment.Conclusions:We replicated prior work showing that Blacks are at increased risk for poorer neurocognitive outcomes post-stroke than Whites. Health literacy and insurance type might be important modifiable factors influencing these differences. (JINS, 2017,23, 640–652)

Racial disparities in cognitive performance exist across the life course, but it is not known whether mediators of disparities differ by age. Understanding sources of cognitive disparities at different ages can inform policies and interventions. Data were obtained for non-Hispanic Black and White respondents to The National Survey of Midlife Development in the United States from 3 age groups: 28-44 (N = 1210; 20% Black); 45-64 (N = 2693; 15% Black); and 65-85 (N = 1298; 11% Black). Moderated mediation models characterized direct and indirect effects of race on episodic memory and executive function composite scores through economic, health, and psychosocial variables as a function of age group. Education, income, chronic health conditions, and external locus of control mediated cognitive disparities across the life course, although income was a stronger mediator at younger ages. Perceived discrimination was a weaker mediator among young adults due to an absence of racial differences in perceived discrimination in that group. Despite multiple indirect effects, there were still significant unexplained effects of race on cognition that were not moderated by age group. Interventional work is needed to determine whether increasing educational attainment and income, and reducing chronic health conditions and perceived constraints among Blacks, reduce cognitive disparities. Targeting income inequality and discrimination (or buffering the impact of those variables) may be differently effective at reducing cognitive disparities at different stages of the adult life course. (PsycINFO Database Record

Objective: To evaluate the association of late-life depression with mild cognitive impairment (MCI) and dementia in a multiethnic community cohort. Design and Setting: A cohort study was conducted in Northern Manhattan, New York, New York. Participants: A total of 2160 community-dwelling Medicare recipients aged 65 years or older were included in the study. Methods: Depression was assessed using the 10-item version of the Center for Epidemiological Studies Depression scale (CES-D) and defined by a CES-D score of 4 or more. We used logistic regression for cross-sectional association analyses and proportional hazards regression for longitudinal analyses. Main Outcome Measures: Mild cognitive impairment dementia, and progression from MCI to dementia were the main outcome measures. We also used subcategories of MCI (amnestic and nonamnestic), and dementia (probable Alzheimer disease and vascular dementia, including possible Alzheimer disease with stroke). Results: Baseline depression was associated with prevalent MCI (odds ratio, 1.4; 95% CI, 1.1-1.9) and dementia (2.2; 1.6-3.1). Baseline depression was associated with an increased risk of incident dementia (hazard ratio [HR], 1.7; 95% CI, 1.2-2.3) but not with incident MCI (0.9; 0.7-1.2). Persons with MCI and coexisting depression at baseline had a higher risk of progression to dementia (HR, 2.0; 95% CI, 1.2-3.4), especially vascular dementia (4.3; 1.1-17.0), but not Alzheimer disease (1.9; 1.0-3.6). Conclusion: The association of depression with prevalent MCI and with progression from MCI to dementia, but not with incident MCI, suggests that depression accompanies cognitive impairment but does not precede it. JAMA Neurol. 2013;70(3):383-389. Published online December 31, 2012. doi:10.1001/jamaneurol.2013.603

Introduction African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. Methods We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7 , identified previously in a LOAD GWAS of AAs. Results Two SNPs at novel loci, rs112404845 ( P = 3.8 × 10 −8 ), upstream of COBL , and rs16961023 ( P = 4.6 × 10 −8 ), downstream of SLC10A2 , obtained genome-wide significant evidence of association with the posterior liability. Discussion An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS.

Background: Previous research has identified multiple risk and protective factors for late onset Alzheimer’s disease (LOAD). However, it is not known whether these risk and protective factors differ for individuals who are cognitively stable versus those already experiencing declines. Objective: This study examined how dementia risk factors differ across subgroups of older adults defined by memory trajectory. This line of research may lead to more individualized risk profiles. Methods: Risk factors for incident LOAD were compared across previously-validated groups of older adults exhibiting different memory trajectories (“Stable-High,” “Stable-Low,” “Decliner,” “Rapid Decliner”) using stratified Cox regressions. Participants included 2,593 racially/ethnically diverse older adults (mean age of 76 at study entry) in the Washington HeightsInwood Columbia Aging Project. Results: Predictors of incident dementia differed across trajectory groups: older age only incurred independent risk in stable groups, education did not incur independent protection in the rapidly declining group, depression only incurred independent risk in the stable-low group, stroke incurred independent risk in the two extreme groups, and APOE-4 only incurred independent risk in the rapidly declining group. Conclusion: The finding that different risk factors for LOAD were associated with specific memory trajectories may reflect the existence of resilience or vulnerability factors that modify the individual influences of risk/protective factors. This study highlights the utility of considering interactions between dementia risk factors and a patient’s unique cognitive history.

Background/Aims: The metabolic syndrome (MeSy) may be related to Alzheimer’s disease (AD). Our aims were to investigate the association of the MeSy with incident dementia in a multiethnic elderly cohort in the United States. Methods: We conducted cross-sectional and prospective analyses in 2,476 men and women aged 65 years and older and with data available on the MeSy and dementia diagnosis in Northern New York City. MeSy was defined by the National Cholesterol Education Program Adult Treatment Program III and the European Group for the Study of Insulin Resistance criteria. Dementia was diagnosed using standard criteria. Results: No association was found between MeSy and prevalent dementia. After 4.4 years of follow-up, 236 individuals of the 1,833 without prevalent dementia developed dementia. MeSy was not associated with incident dementia. Of the components of the MeSy, diabetes and hyperinsulinemia were associated with an increased risk of incident AD [hazard ratio 1.4 (95% CI 1.0–2.1), and hazard ratio 1.4 (95% CI 0.9–2.7), respectively] and dementia associated with stroke [hazard ratio 1.9 (95% CI 1.1–3.1), and hazard ratio 2.3 (95% CI 1.1–4.7), respectively]. Conclusions: The MeSy was not associated with an increased dementia risk in a multiethnic elderly cohort, but diabetes and hyperinsulinemia were. In the elderly, examining diabetes and hyperinsulinemia separately may be preferable to using the MeSy as a risk factor.

Importance Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. Objective To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. Design, Setting, and Participants Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer’s Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project–Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. Main Outcomes and Measures The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. Results The African American cohort had a low degree of inbreeding ( F ~ 0.006). In the Alzheimer’s Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb ( P = .004) or greater than 3 Mb ( P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project–Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. Conclusions and Relevance To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.

Objectives: To determine whether older adults with type 2 diabetes mellitus and cognitive dysfunction have poorer metabolic control of glycosylated hemoglobin, systolic blood pressure, and low-density lipoprotein cholesterol than those without cognitive dysfunction. Design: Prospective cohort study. Setting: A minority cohort in New York City previously recruited for a trial of telemedicine. Participants: Persons aged 73.0 ± 3.0 (N = 613; 69.5% female; 82.5% Hispanic, 15.5% non-Hispanic black). Measurements: Participants were classified with executive or memory dysfunction based on standardized score cutoffs (

Language facilitates communication and efficient encoding of thought and experience. Because of its essential role in early childhood development, in educational achievement and in subsequent life adaptation, language was included as one of the subdomains in the NIH Toolbox for the Assessment of Neurological and Behavioral Function Cognition Battery (NIHTB-CB). There are many different components of language functioning, including syntactic processing (i.e., morphology and grammar) and lexical semantics. For purposes of the NIHTB-CB, two tests of language—a picture vocabulary test and a reading recognition test—were selected by consensus based on literature reviews, iterative expert input, and a desire to assess in English and Spanish. NIHTB-CB’s picture vocabulary and reading recognition tests are administered using computer adaptive testing and scored using item response theory. Data are presented from the validation of the English versions in a sample of adults ages 20–85 years (Spanish results will be presented in a future publication). Both tests demonstrated high test–retest reliability and good construct validity compared to corresponding gold-standard measures. Scores on the NIH Toolbox measures were consistent with age-related expectations, namely, growth in language during early development, with relative stabilization into late adulthood. (JINS, 2014, 20, 1–10)

Objectives: To determine whether depressive symptoms typically precede or follow memory declines. Design: An autoregressive latent trajectory model was used to examine the direction of the relationship between depressive symptoms and memory decline observed over 12 years. Setting: Washington/Hamilton Heights Inwood Columbia Aging Project, a community-based longitudinal study of aging and dementia in northern Manhattan. Participants: Older adults initially without dementia (n = 2,425). Measurements: Memory composite scores were computed from three subscores of the Selective Reminding Test. Depressive symptoms were assessed using a 10-item version of the Center for Epidemiologic Studies Depression Scale. Analyses controlled for age, sex, recruitment wave, education, black race, and Hispanic ethnicity measured at baseline and chronic disease burden measured at each study visit. Results: Initial depressive symptoms predicted worse memory scores at the second study visit (B weight = -0.03; P = .003) and accelerated memory decline over the entire study period (B weight = -0.02; P = .03). Memory scores did not predict subsequent depressive symptoms. Conclusion: These findings suggest that depressive symptoms precede memory decline, but not vice versa, in late life. This pattern of results is consistent with hypotheses that depression is a prodrome of dementia or a causal contributor to memory decline. Clinicians should be aware that depressive symptoms may represent an early indicator not only of dementia, as reported previously, but also of memory decline more generally.

International audience; BACKGROUND: A large number of longitudinal studies of population-based ageing cohorts are in progress internationally, but the insights from these studies into the risk and protective factors for cognitive ageing and conditions like mild cognitive impairment and dementia have been inconsistent. Some of the problems confounding this research can be reduced by harmonising and pooling data across studies. COSMIC (Cohort Studies of Memory in an International Consortium) aims to harmonise data from international cohort studies of cognitive ageing, in order to better understand the determinants of cognitive ageing and neurocognitive disorders.Methods/design: Longitudinal studies of cognitive ageing and dementia with at least 500 individuals aged 60 years or over are eligible and invited to be members of COSMIC. There are currently 17 member studies, from regions that include Asia, Australia, Europe, and North America. A Research Steering Committee has been established, two meetings of study leaders held, and a website developed. The initial attempts at harmonising key variables like neuropsychological test scores are in progress. DISCUSSION: The challenges of international consortia like COSMIC include efficient communication among members, extended use of resources, and data harmonisation. Successful harmonisation will facilitate projects investigating rates of cognitive decline, risk and protective factors for mild cognitive impairment, and biomarkers of mild cognitive impairment and dementia. Extended implications of COSMIC could include standardised ways of collecting and reporting data, and a rich cognitive ageing database being made available to other researchers. COSMIC could potentially transform our understanding of the epidemiology of cognitive ageing, and have a world-wide impact on promoting successful ageing.

Background: In order to develop health outcomes measures that are relevant and applicable to the general population, it is essential to consider the needs and requirements of special subgroups, such as the young, elderly, disabled, and people of different ethnic and cultural backgrounds, within that population. Methods: The NIH Toolbox project convened several working groups to address assessment issues for the following subgroups: pediatric, geriatric, cultural, non–English-speaking, and disabled. Each group reviewed all NIH Toolbox instruments in their entirety. Results: Each working group provided recommendations to the scientific study teams regarding instrument content, presentation, and administration. When feasible and appropriate, instruments and administration procedures have been modified in accordance with these recommendations. Conclusion: Health outcome measurement can benefit from expert input regarding assessment considerations for special subgroups.

Background Amnestic mild cognitive impairment (aMCI) is associated with an elevated risk of progressing to Alzheimer's disease. Much less is known about the course of dysexecutive mild cognitive impairment (dMCI). The goals of this study were to determine how the profile of cognitive deficits differs over time between patients with dMCI and aMCI, and control subjects; if the type of dementia differs between dMCI and aMCI in patients who progress to dementia; and if dMCI is more associated with stroke and white matter hyperintensity on magnetic resonance imaging (MRI) than aMCI. Methods The authors undertook a prospective evaluation of an inception cohort of 1167 ethnically diverse elders recruited from an urban community-based sample monitored with clinical and neuropsychological testing for an average of 4.5 years (standard deviation, 0.8 year). A subset of the subjects underwent MRI. We compared four groups of MCI patients: single-domain amnestic and dysexecutive MCI, and multiple-domain MCI with and without executive dysfunction. Results Compared with aMCI, dMCI was less likely to involve other areas of cognition over time and progress to dementia. None of the 33 single-domain dMCI patients progressed to dementia. The presence of executive dysfunction in multiple-domain MCI did not increase risk of progression to dementia. Patients with multiple-domain MCI with executive dysfunction who progressed to dementia were less likely to have an Alzheimer's–type dementia than MCI patients without executive dysfunction. Patients with dMCI were more likely to experience stroke, but not white matter hyperintensity, detected via MRI than patients with aMCI. Conclusions dMCI appears to follow a different course, and is less associated with Alzheimer's disease and more associated with stroke than aMCI.

The objective of this study was to compare the demographic and vascular characteristics and APOE genotypes of a dysexecutive subgroup of Alzheimer disease (AD) with an amnestic subgroup of AD early in the disease course. A total of 2224 participants from the National Alzheimer's Coordinating Center database who carried a diagnosis of mild cognitive impairment (n=1188) or mild AD (clinical dementia rating ≤1) (n=1036) were included in this study. A subset of the mild cognitive impairment (n=61) and mild AD (n=79) participants underwent an autopsy. A dysexecutive subgroup (n=587) was defined as having executive performance >1 SD worse than memory performance, and an amnestic subgroup (n=549) was defined conversely. Among the autopsy subset, the odds of an AD pathologic diagnosis were compared in the 2 subgroups. The demographics, APOE[Latin Small Letter Open E]4 status, and vascular risk factors were compared in the 2 subgroups. Among the autopsy subset, the odds of having an AD pathologic diagnosis did not differ between the dysexecutive and amnestic subgroups. Under an additive model, participants in the dysexecutive subgroup possessed the APOE[Latin Small Letter Open E]4 allele less frequently compared with those in the amnestic subgroup. The dysexecutive subgroup had a history of hypertension less frequently compared with the amnestic subgroup. These distinct characteristics add to accumulating evidence that a dysexecutive subgroup of AD may have a unique underlying pathophysiology.