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Background and Purpose: Brain arterial diameters are markers of cerebrovascular disease. Demographic and anatomical factors may influence arterial diameters. We hypothesize that age, sex, height, total cranial volume (TCV), and persistent fetal posterior cerebral artery (fPCA) correlate with brain arterial diameters across populations., Methods: Participants had a time-of-flight MRA from nine international cohorts. Arterial diameters of the cavernous internal carotid arteries (ICA), middle cerebral arteries (MCA), and basilar artery (BA) were measured using LAVA software. Regression models assessed the association between exposures and brain arterial diameters., Results: We included 6,518 participants (mean age: 70 ± 9 years; 41% men). Unilateral fPCA was present in 13.2% and bilateral in 3.2%. Larger ICA, MCA, and BA diameters correlated with older age (Weighted average [WA] per 10 years: 0.18 mm, 0.11 mm, and 0.12 mm), male sex (WA: 0.24 mm, 0.13 mm, and 0.21 mm), and TCV (WA: for one TCV standard deviation: 0.24 mm, 0.29 mm, and 0.18 mm). Unilateral and bilateral fPCAs showed a positive correlation with ICA diameters (WA: 0.39 mm and 0.73 mm) and negative correlation with BA diameters (WA: -0.88 mm and -1.73 mm). Regression models including age, sex, TCV, and fPCA explained on average 15%, 13%, and 25% of the ICA, MCA, and BA diameter interindividual variation, respectively. Using height instead of TCV as a surrogate of head size decreased the R-squared by 3% on average., Conclusion: Brain arterial diameters correlated with age, sex, TCV, and fPCA. These factors should be considered when defining abnormal diameter cutoffs across populations., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Depressive symptoms are associated with higher risk of dementia, but how they impact cognition in diverse populations is unclear., Methods: Asian, Black, Latino, or White participants (n = 2227) in the Kaiser Healthy Aging and Diverse Life Experiences (age 65+) and the Study of Healthy Aging in African Americans (age 50+) underwent up to three waves of cognitive assessments over 4 years. Multilevel models stratified by race/ethnicity were used to examine whether depressive symptoms were associated with cognition or cognitive decline and whether associations differed by race/ethnicity., Results: Higher depressive symptoms were associated with lower baseline verbal episodic memory scores (-0.06, 95% CI: -0.12, -0.01; -0.15, 95% CI: -0.25, -0.04), and faster decline annually in semantic memory (-0.04, 95% CI: -0.07, -0.01; -0.10, 95% CI: -0.15, -0.05) for Black and Latino participants. Depressive symptoms were associated with lower baseline but not decline in executive function., Discussion: Depressive symptoms were associated with worse cognitive outcomes, with some evidence of heterogeneity across racial/ethnic groups., Highlights: We examined whether baseline depressive symptoms were differentially associated with domain-specific cognition or cognitive decline by race/ethnicity. Depressive symptoms were associated with worse cognitive scores for all racial/ethnic groups across different domains examined. Higher depressive symptoms were associated with faster cognitive decline for semantic memory for Black and Latino participants. The results suggest a particularly harmful association between depressive symptoms and cognition in certain racial/ethnic groups., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: This study seeks to examine neighborhood characteristics, physical activity, and health status and their roles in promoting healthy cognitive aging. Methods: Using data from the REasons for Geographic And Racial Difference in Stroke (REGARDS) study ( N =10,289, mean age=73.4 years), we used multilevel linear regression to examine the relationships between walkable neighborhoods (both objectively measured and subjective perceptions), walking behavior, physical activity, health status, and cognitive function. Results: Engaging in any moderate physical activity (β=0.47, p < 0.001), having better health status (β=0.02, p < 0.001), living in neighborhoods with greater street connectivity (β=0.15, p < 0.05), and positive perceptions of neighborhood traffic ( p < 0.01) and parks ( p < 0.05), were associated with higher cognitive function. Residence in socioeconomically disadvantaged neighborhoods (β=-0.01, p < 0.01) was negatively associated with cognitive function . Discussion: Both perceived and objective features of walkable environments may have consequences for cognitive health, and can inform the development of health promoting communities.

Racial residential segregation is associated with multiple adverse health outcomes in Black individuals. Yet, the influence of structural racism and racial residential segregation on brain aging is less understood. In this study, we investigated the association between cumulative exposure to racial residential segregation over 25 years (1985-2010) in young adulthood, as measured by the Getis-Ord Gi* statistic, and year 25 measures of brain volume (cerebral, gray matter, white matter, and hippocampal volumes) in midlife. We studied 290 Black participants with available brain imaging data who were enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a prospective cohort study. CARDIA investigators originally recruited 2,637 Black participants aged 18-30 years from 4 field centers across the United States. We conducted analyses using marginal structural models, incorporating inverse probability of treatment weighting and inverse probability of censoring weighting. We found that compared with low/medium segregation, greater cumulative exposure to a high level of racial residential segregation throughout young adulthood was associated with smaller brain volumes in general (e.g., for cerebral volume, β = -0.08, 95% confidence interval: -0.15, -0.02) and with a more pronounced reduction in hippocampal volume, though results were not statistically significant. Our findings suggest that exposure to segregated neighborhoods may be associated with worse brain aging., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

Background: Epidemiological studies utilize residential histories to assess environmental exposure risk. The validity from using commercially-sourced residential histories within national longitudinal studies remains unclear. Our study assessed predictors of non-agreement between baseline addresses from the commercially-sourced LexisNexis database and participants in the national longitudinal study, REasons for Geographic and Racial Differences in Stroke (REGARDS). Additionally, we assessed differences in stroke risk by neighborhood socioeconomic score (nSES) based on participant reported address compared to nSES from LexisNexis/REGARDS matched baseline address., Methods: From January 2003-October 2007, REGARDS enrolled 30,239 black and white adults aged 45 and older within the continental United States and collected their baseline address. ArcGIS Desktop 10.5.1 with ESRI 2016 Business Analyst Data was used to geocode baseline addresses from LexisNexis and REGARDS. Logistic regression was used to estimate the likelihood that LexisNexis address matched REGARDS baseline address for each participant. Survival analysis was used to estimate association between nSES and incident stroke., Results: Approximately 91% of REGARDS participants had a LexisNexis address. Of these geocoded addresses, 93% of REGARDS baseline addresses matched LexisNexis addresses. Odds of agreement between LexisNexis and REGARDS was higher for older-aged participants (OR = 1.02 per year, 95% CI: 1.01, 1.02), blacks compared to whites (OR = 1.16, 95% CI: 1.05, 1.29), females compared to males (OR = 1.15, 95% CI: 1.04, 1.26), participants with an income of $34k-74k compared to an income less than $20k (OR = 1.62, 95% CI: 1.39, 1.89). Odds of agreement were lower for residents in Midwest compared to residents in the south (OR = 0.82, 95% CI: 0.73, 0.94). No significant differences in nSES-stroke associations were observed between REGARDS only and LexisNexis/REGARDS matched addresses; however, differences in interactions were observed., Conclusion: Agreement between LexisNexis and REGARDS addresses varied by sociodemographic groups, potentially introducing bias in studies reliant on LexisNexis alone for residential address data., Competing Interests: None., (Published by Elsevier Ltd.)

Objectives: Myocyte 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., Method: Participants 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., Results: Single 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)., Discussion: MEF2C 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sunderaraman, Cosentino, Schupf, Manly, Gu and Barral.)

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)-ε4, 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., (© 2020 the Alzheimer's Association.)

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., Competing Interests: The authors have no conflicts of interest to disclose., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Americans have significantly poorer health outcomes and shorter longevity than citizens of other industrialized nations. Poverty is a major driver of these poor health outcomes in the United States. Innovative anti-poverty policies may help reduce economic malaise thereby increasing the health and longevity of the most vulnerable Americans. However, there is no consensus framework for studying the health impacts of anti-poverty social policies. In this paper, we describe a case study in which leading global experts systematically: (1) developed a conceptual model that outlines the potential pathways through which a social policy influences health, (2) fits outcome measures to this conceptual model, and (3) estimates an optimal time frame for collection of the selected outcome measures. This systematic process, called the Delphi method, has the potential to produce estimates more quickly and with less bias than might be achieved through expert panel discussions alone. Our case study is a multi-component randomized-controlled trial (RCT) of a workforce policy called MyGoals for Healthy Aging., Competing Interests: The authors declare no conflict of interest.

Importance: Personality phenotype has been associated with subsequent dementia in studies of older adults. However, neuropathologic changes often precede cognitive symptoms by many years and may affect personality itself. Therefore, it is unclear whether supposed dementia-prone personality profiles (high neuroticism and low conscientiousness) are true risk factors or merely reflections of preexisting disease., Objectives: To examine whether personality during adolescence-a time when preclinical dementia pathology is unlikely to be present-confers risk of dementia in later life and to test whether associations could be accounted for by health factors in adolescence or differed across socioeconomic status (SES)., Design, Setting, and Participants: Cohort study in the United States. Participants were members of Project Talent, a national sample of high school students in 1960. Individuals were identified who received a dementia-associated International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code during any year between 2011 and 2013. The dates of our analysis were March 2018 to May 2019., Exposures: Ten personality traits were measured by the 150-item Project Talent Personality Inventory. Socioeconomic status was measured by a composite based on parental educational level, income, occupation, and property ownership. Participants were also surveyed on demographic factors and height and weight., Main Outcomes and Measures: Medicare records were collected, with dementia diagnoses in the period of 2011 to 2013 classified according to the US Centers for Medicare & Medicaid Services ICD-9-based algorithm. Cox proportional hazards regression models estimated the relative risk of dementia based on the 10 personality traits, testing interactions with SES and adjusting for demographic confounders., Results: The sample of 82 232 participants was 50.1% female, with a mean (SD) age of 15.8 (1.7) years at baseline and 69.5 (1.2) years at follow-up. Lower risk of dementia was associated with higher levels of vigor (hazard ratio for 1 SD, 0.93; 95% CI, 0.90-0.97; P < .001). Calm and maturity showed protective associations with later dementia that increased with SES. At 1 SD of SES, calm showed a hazard ratio of 0.89 (95% CI, 0.84-0.95; P < .001 for the interaction) and maturity showed a hazard ratio of 0.90 (95% CI, 0.85-0.96; P = .001 for the interaction)., Conclusions and Relevance: This study's findings suggest that the adolescent personality traits associated with later-life dementia are similar to those observed in studies of older persons. Moreover, the reduction in dementia risk associated with a calm and mature adolescent phenotype may be greater at higher levels of SES. Personality phenotype may be a true independent risk factor for dementia by age 70 years, preceding it by almost 5 decades and interacting with adolescent socioeconomic conditions.

Introduction: Odor identification deficits characterize Alzheimer's disease and other dementias. We examined if intact performance on brief cognitive and odor identification tests predicts lack of transition to dementia., Methods: In an urban community, 1037 older adults without dementia completed the 40-item University of Pennsylvania Smell Identification Test, which includes the 12-item Brief Smell Identification Test (B-SIT). Data from 749 participants followed up for 4 years were analyzed., Results: In covariate-adjusted survival analyses, impairment on the Blessed Orientation Memory Concentration Test and B-SIT each predicted dementia (n = 109), primarily Alzheimer's disease (n = 101). Among participants with intact olfactory (B-SIT ≥ 11/12 correct) and cognitive (Blessed Orientation Memory Concentration Test ≤ 5/28 incorrect) ability, 3.4% (4/117) transitioned to dementia during follow-up with no transitions in the 70-75 and 81-83 years age group quartiles., Discussion: Odor identification testing adds value to global cognitive testing, and together can identify individuals who rarely transition to dementia, thereby avoiding unnecessary diagnostic investigation., (© 2019 the Alzheimer's Association.)

The objective of this study was to determine the long-term test-retest reliability of the University of Pennsylvania Smell Identification Test (UPSIT), and its individual items, in cognitively intact older adults. A community sample of older adults received a neuropsychological test battery, including the 12-item, 6-trial Selective Reminding Test (SRT). The UPSIT was administered at baseline and follow-up that occurred between 1 and 4 years after baseline. UPSIT scores of participants who were cognitively intact and did not decline cognitively were examined for test-retest reliability. In 92 older adults with mean age 77.6 years followed for 2.79 (standard deviation [SD] 0.69) years, mean UPSIT score declined from 30.29 (SD 5.83) to 27.80 (SD 5.50). In linear mixed models that adjusted for time, age, sex, and education, intraclass correlation coefficients for UPSIT were 0.65, SRT delayed recall 0.59, and SRT total immediate recall 0.49. Among 4 possible response combinations, the largest proportion of participants had correct responses at both visits for 35 out of 40 items. Consistency of item responses ranged from 50% to 90% across the 2 time points. The long-term test-retest reliability of the UPSIT was moderately strong without practice effects over long periods of time in older adults. These results provide indirect support to prior findings on odor identification impairment predicting cognitive decline and dementia, and suggest potential use of olfactory testing as a biomarker in prevention and treatment trials of cognitive enhancers., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Sickle cell anemia may be associated with cognitive dysfunction, and some complications of sickle cell anemia might affect those with sickle cell trait (SCT), so we hypothesized that SCT is a risk factor for cognitive impairment., Methods: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study enrolled a national cohort of 30,239 white and black Americans from 2003 to 7, who are followed every 6 months. Baseline and annual global cognitive function testing used the Six-Item Screener (SIS), a validated instrument (scores range 0-6; ≤ 4 indicates cognitive impairment). Participants with baseline cognitive impairment and whites were excluded. Logistic regression was used to calculate the association of SCT with incident cognitive impairment, adjusted for risk factors. Linear mixed models assessed multivariable-adjusted change in test scores on a biennially administered 3-test battery measuring learning, memory, and semantic and phonemic fluency., Findings: Among 7743 participants followed for a median of 7·1 years, 85 of 583 participants with SCT (14·6%) developed incident cognitive impairment compared to 902 of 7160 (12·6%) without SCT. In univariate analysis, the odds ratio (OR) of incident cognitive impairment was 1·18 (95% CI: 0·93, 1·51) for those with SCT vs. those without. Adjustment did not impact the OR. There was no difference in change on 3-test battery scores by SCT status (all p  > 0·11)., Interpretation: In this prospective cohort study of black Americans, SCT was not associated with incident cognitive impairment or decline in test scores of learning, memory and executive function., Funding: National Institutes of Health, American Society of Hematology.

Introduction: We tested the hypothesis that brain arterial dilatation increases the risk of Alzheimer's dementia (AD)., Methods: We studied dementia-free participants in the Washington Heights-Inwood Columbia Aging Project who had a brain MRI and post-MRI dementia adjudication. We measured the axial T2-proton density diameters of the intracranial carotids and basilar diameters and used Cox models to obtain AD hazard ratios and 95% intervals., Results: Of 953 participants (mean age 77 ± 7 y, women 64%, 71% nonwhite) followed on average for 3 ± 3 years, 76 (8%) developed AD. In a model adjusted for demographics, vascular risks, apolipoprotein E (APOE)-ε4, and white matter hyperintensities, larger carotid diameters increased the risk of AD, defined categorically as ≥ 90th percentile (HR 4.34, 1.70-11.11) or continuously (HR 1.44 per SD, 1.07-1.94)., Discussion: Understanding the pathophysiology of the association between AD and brain arterial dilatation may reveal new clues to the vascular contributions to AD., (Copyright © 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objectives: Describe novel methods for ascertaining verbal fluency in a large national sample of adults, examine demographic factors influencing performance, and compare scores to studies using in-person assessment., Methods/design: Participants were from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a national, population-based, longitudinal study of stroke in adults aged 45 years and older. Letter and semantic fluency were gathered, using Letter "F" and Animal Naming, via a telephone-based assessment with computer-assisted scoring of digital recordings., Results: Initial letter and semantic fluency scores were obtained on 18 505 and 18 072 participants, respectively. For both fluency tests, scores were normally distributed. Younger age and more years of education were associated with better performances (p < 0.0001). The mean and standard deviation for matched subgroups, based on age, gender, and education, were quite comparable with scores reported out of samples using an in-person administration format. Telephone-based assessment also allowed for a level of quality control not available via in-person measurement., Conclusions: Telephone-based assessment of verbal fluency and computer-assisted scoring programs designed for this study facilitated large-scale data acquisition, storage, and scoring of protocols. The resulting scores have similar characteristics to those obtained by traditional methods. These findings extend validation of cognitive assessment methods, using survey research staff and computer-assisted technology for test administration., (© 2018 John Wiley & Sons, Ltd.)

Background: Working memory (WM) is often assessed with serial order tests such as repeating digits backward. In prior dementia research using the Backward Digit Span Test (BDT), only aggregate test performance was examined., Objective: The current research tallied primacy/recency effects, out-of-sequence transposition errors, perseverations, and omissions to assess WM deficits in patients with mild cognitive impairment (MCI)., Methods: Memory clinic patients (n = 66) were classified into three groups: single domain amnestic MCI (aMCI), combined mixed domain/dysexecutive MCI (mixed/dys MCI), and non-MCI where patients did not meet criteria for MCI. Serial order/WM ability was assessed by asking participants to repeat 7 trials of five digits backwards. Serial order position accuracy, transposition errors, perseverations, and omission errors were tallied., Results: A 3 (group)×5 (serial position) repeated measures ANOVA yielded a significant group×trial interaction. Follow-up analyses found attenuation of the recency effect for mixed/dys MCI patients. Mixed/dys MCI patients scored lower than non-MCI patients for serial position 3 (p < 0.003) serial position 4 (p < 0.002); and lower than both group for serial position 5 (recency; p < 0.002). Mixed/dys MCI patients also produced more transposition errors than both groups (p < 0.010); and more omissions (p < 0.020), and perseverations errors (p < 0.018) than non-MCI patients., Conclusions: The attenuation of a recency effect using serial order parameters obtained from the BDT may provide a useful operational definition as well as additional diagnostic information regarding working memory deficits in MCI.

Objective: To investigate the association between a genetic risk score (GRS) and familial late-onset Alzheimer disease (LOAD) and its predictive value in families multiply affected by the disease., Methods: Using data from the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease (National Institute on Aging-Late-Onset Alzheimer's Disease Family Study), mixed regression models tested the association of familial LOAD with a GRS based on single nucleotide polymorphisms (SNPs) previously associated with LOAD. We modeled associations using unweighted and weighted scores with estimates derived from the literature. In secondary models, we adjusted subsequent models for presence of the APOE ε4 allele and further tested the interaction between APOE ε4 and the GRS. We constructed a similar GRS in a cohort of Caribbean Hispanic families multiply affected by LOAD by selecting the SNP with the strongest p value within the same regions., Results: In the NIA-LOAD families, the GRS was significantly associated with LOAD (odds ratio [OR] 1.29; 95% confidence interval 1.21-1.37). The results did not change after adjusting for APOE ε4. In Caribbean Hispanic families, the GRS also significantly predicted LOAD (OR 1.73; 1.57-1.93). Higher scores were associated with lower age at onset in both cohorts., Conclusions: High GRS increases the risk of familial LOAD and lowers the age at onset, regardless of ethnic group., (© 2017 American Academy of Neurology.)

Importance: The contribution of cardiovascular disease (CV) and cerebrovascular disease to the risk for late-onset Alzheimer disease (LOAD) has been long debated. Investigations have shown that antecedent CV risk factors increase the risk for LOAD, although other investigations have failed to validate this association., Objective: To study the contribution of CV risk factors (type 2 diabetes, hypertension, and heart disease) and the history of stroke to LOAD in a data set of large families multiply affected by LOAD., Design, Setting, and Participants: The National Institute on Aging Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease family study (hereinafter referred to as NIA-LOAD study) is a longitudinal study of families with multiple members affected with LOAD. A multiethnic community-based longitudinal study (Washington Heights-Inwood Columbia Aging Project [WHICAP]) was used to replicate findings. The 6553 participants in the NIA-LOAD study were recruited from 23 US Alzheimer disease centers with ongoing data collection since 2003; the 5972 WHICAP participants were recruited at Columbia University with ongoing data collection since 1992. Data analysis was performed from 2003 to 2015., Main Outcomes and Measures: Generalized mixed logistic regression models tested the association of CV risk factors (primary association) with LOAD. History of stroke was used for the secondary association. A secondary model adjusted for the presence of an apolipoprotein E (APOE) ε4 allele. A genetic risk score, based on common variants associated with LOAD, was used to account for LOAD genetic risk beyond the APOE ε4 effect. Mediation analyses evaluated stroke as a mediating factor between the primary association and LOAD., Results: A total of 6553 NIA-LOAD participants were included in the analyses (4044 women [61.7%]; 2509 men [38.3%]; mean [SD] age, 77.0 [9] years), with 5972 individuals from the WHICAP study included in the replication sample (4072 women [68.2%]; 1900 men [31.8%]; mean [SD] age, 76.5 [7.0] years). Hypertension was associated with decreased LOAD risk (odds ratio [OR], 0.63; 95% CI, 0.55-0.72); type 2 diabetes and heart disease were not. History of stroke conferred greater than 2-fold increased risk for LOAD (OR, 2.23; 95% CI, 1.75-2.83). Adjustment for APOE ε4 did not alter results. The genetic risk score was associated with LOAD (OR, 2.85; 95% CI, 2.05-3.97) but did not change the independent association of LOAD with hypertension or stroke. In the WHICAP sample, hypertension was not associated with LOAD (OR, 0.99; 95% CI, 0.88-1.11), whereas history of stroke increased the risk for LOAD (OR, 1.96; 95% CI, 1.56-2.46). The effect of hypertension on LOAD risk was also mediated by stroke in the NIA-LOAD and the WHICAP samples., Conclusions and Relevance: In familial and sporadic LOAD, a history of stroke was significantly associated with increased disease risk and mediated the association between selected CV risk factors and LOAD, which appears to be independent of the LOAD-related genetic background., Competing Interests: Dr Boeve reports serving as an investigator for clinical trials sponsored by Cephalon, Inc, Allon Pharmaceuticals, and GE Healthcare; receiving royalties from the publication of a book titled Behavioral Neurology of Dementia (Cambridge Medicine; 2009); receiving honoraria from the American Academy of Neurology; serving on the Scientific Advisory Board of the Tau Consortium; and receiving research support from the National Institute on Aging (NIA) (grants P50 AG016574, U01 AG006786, RO1 AG032306, RO1 AG041797) and the Mangurian Foundation. Dr Farlow reports receiving grant and research support from Accera, Biogen, Eisai Med Res, Eli Lilly & Company, Genentech, MedAvante/AstraZeneca, and Navidea; serving on the speaker's bureau at Eisai Med Res, Pfizer, Inc, Forest, Novartis, and Eli Lilly & Company; serving on the consultant or advisory boards at Accera, Alltech, Avanir, Eisai Med Res, Inc, Helicon, Medavante, Medivation, Inc, Merck and Co, Inc, Novartis, Pfizer, Inc, Prana Biotech, QR Pharma, Roche, Sanofi-Aventis, Schering-Plough, Toyama Pharm, Eli Lilly & Company, UCB Pharma, and Elan. Dr Rosenberg reports holding a US patent for Amyloid β Gene Vaccines and serving on the editorial board of the Journal of the Neurological Sciences. Disclosures:No other disclosures were reported.

Background: Depression has been associated with increased risk of death. However, there is lack of studies exploring such relationship in the context of dementia. Given the high prevalence of both depression and Alzheimer's Disease (AD), investigating their temporal association with mortality is of public health relevance., Methods: Longitudinal data from the WHICAP study were analyzed (1958 individuals aged ≥65 years). Depressive symptoms were assessed with the 10-item Center for Epidemiologic Studies Depression Scale (CES-D). Respondents were identified as having AD if they satisfied the criteria of the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Cox regressions analyses were performed to determine the association between depressive symptoms and risk of all-cause mortality using the overall sample, and by AD status., Results: Depressive symptoms were significantly associated with higher mortality risk after adjusting for all potential covariates in the overall sample (HR=1.22; 95% CI=1.02, 1.46) and in individuals with incident AD (HR=1.88; 95% CI=1.12, 3.18)., Limitations: The CES-D does not measure clinical depression but depressive symptomatology. Since those who were exposed to known risk factors for mortality are likely to die prematurely, our results may have been skewed to the individuals with longer survival., Conclusions: Strategies focusing on prevention and early treatment of depression in the elderly may have a beneficial effect not only on patient quality of life and disability, but may also increase survival in the context of AD., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: This study aimed to examine the association between self-reported sleep disordered breathing (SDB) ("awaken short of breath or with a headache") and mortality in a large and ethnically diverse group of community-dwelling elderly people., Methods: A total of 1288 participants, 65 years and older, were examined longitudinally. Sleep problems were estimated using the Medical Outcomes Study Sleep Scale examining sleep disturbance, snoring, awaken short of breath or with a headache, sleep adequacy, and sleep somnolence. Cox regression analysis was used to examine the association between sleep problems and mortality. Age, gender, education, ethnicity, and body mass index were included as covariates. In further analyses we included hypertension, diabetes, heart disease, and stroke as additional covariates., Results: The participants were followed for up to 6 years (mean = 2.9, standard deviation = 1.1), and 239 (18.6%) participants died during the follow-up. In unadjusted models, SDB at the initial visit was associated with mortality (hazard ratio [HR] = 1.37; 95% confidence interval [CI] 1.21-1.55; P < .0001). After adjusting for all the covariates, the relationship between SDB and mortality remained significant (HR = 1.48; 95% CI 1.29-1.70; P < .0001). Participants with Caribbean-Hispanic ancestry have higher risk for mortality., Conclusions: Our results suggest that SDB is a risk factor for mortality in a large and ethnically diverse group of older adults, independent of demographic and clinical factors. Further research is needed to examine the underlying mechanisms of this association., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to examine the association between self-reported sleep problems and cognitive decline in community-dwelling older people. We hypothesized that daytime somnolence predicts subsequent cognitive decline., Methods: This is a longitudinal study in a 3.2-year follow-up, with 18-month intervals. The setting is the Washington Heights-Inwood Community Aging Project. There were 1098 participants, who were over 65 years old and recruited from the community. Sleep problems were estimated using five sleep categories derived from the RAND Medical Outcome Study Sleep Scale: sleep disturbance, snoring, awaken short of breath/with a headache, sleep adequacy, and daytime somnolence. Four distinct cognitive composite scores were calculated: memory, language, speed of processing, and executive functioning. We used generalized estimating equations analyses with cognitive scores as the outcome, and time, sleep categories and their interactions as the main predictors. Models were initially unadjusted and then adjusted for age, gender, education, ethnicity, depression, and apolipoprotein E-ε4 genotype., Results: Increased daytime somnolence (including feeling drowsy/sleepy, having trouble staying awake, and taking naps during the day) was linked to slower speed of processing both cross-sectionally (B = -0.143, p = 0.047) and longitudinally (B = -0.003, p = 0.027). After excluding the demented participants at baseline, the results remained significant (B = -0.003, p = 0.021)., Conclusions: Our findings suggest that daytime somnolence may be an early sign of cognitive decline in the older population., (Copyright © 2015 John Wiley & Sons, Ltd.)

Diabetes and hyperinsulinemia may be risk factors for Alzheimer's disease (AD). We conducted a pilot study of metformin, a medication efficacious in treating and preventing diabetes while reducing hyperinsulinemia, among persons with amnestic mild cognitive impairment (aMCI) with the goal of collecting preliminary data on feasibility, safety, and efficacy. Participants were 80 men and women aged 55 to 90 years with aMCI, overweight or obese, without treated diabetes. We randomized participants to metformin 1000 mg twice a day or matching placebo for 12 months. The co-primary clinical outcomes were changes from baseline to 12 months in total recall of the Selective Reminding Test (SRT) and the score of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). The secondary outcome was change in relative glucose uptake in the posterior cingulate-precuneus in brain fluorodeoxyglucose positron emission tomography. Change in plasma Aβ42 was an exploratory outcome. The mean age of participants was 65 years. Fifty percent of participants were women. The only baseline variable that was different between the arms was the ADAS-Cog. Metformin could not be tolerated by 7.5% of participants; 15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum dose. There were no serious adverse events related to metformin. The 7.5% of persons who did not tolerate metformin reported gastrointestinal symptoms. After adjusting for baseline ADAS-cog, changes in total recall of the SRT favored the metformin group (9.7±8.5 versus 5.3±8.5; p = 0.02). Differences for other outcomes were not significant. A larger trial seems warranted to evaluate the efficacy and cognitive safety of metformin in prodromal AD.

Background: Changes in criteria and differences in populations studied and methodology have produced a wide range of prevalence estimates for mild cognitive impairment (MCI)., Methods: Uniform criteria were applied to harmonized data from 11 studies from USA, Europe, Asia and Australia, and MCI prevalence estimates determined using three separate definitions of cognitive impairment., Results: The published range of MCI prevalence estimates was 5.0%-36.7%. This was reduced with all cognitive impairment definitions: performance in the bottom 6.681% (3.2%-10.8%); Clinical Dementia Rating of 0.5 (1.8%-14.9%); Mini-Mental State Examination score of 24-27 (2.1%-20.7%). Prevalences using the first definition were 5.9% overall, and increased with age (P < .001) but were unaffected by sex or the main races/ethnicities investigated (Whites and Chinese). Not completing high school increased the likelihood of MCI (P ≤ .01)., Conclusion: Applying uniform criteria to harmonized data greatly reduced the variation in MCI prevalence internationally.

We aimed to examine the association between Apolipoprotein E (APOE) and sleep disturbances. This is a cross-sectional study, from the Washington Heights-Inwood Community Aging Project (WHICAP). A total of 1944 non-demented older adults took part in the study. Sleep dysfunction was measured using sleep categories derived from the Medical Outcomes Study Sleep Scale. Genetic association between APOE-ϵ4 genotype and sleep disturbances was assessed using unadjusted linear regression models. Secondary analyses were conducted adjusting for age, sex, education, ethnicity and body mass index (BMI). In the unadjusted model, individuals carrying the APOE-ϵ4 allele showed lower levels of snoring (β=-0.02, SE=0.01, p=0.010) and sleep apnea (β=-0.01, SE=0.01, p=0.037) when compared to non-ϵ4 carriers. After covariates' adjustment, ϵ4 carriers demonstrated stronger association with lower levels of both snoring (β=-0.02, SE=0.01, p=0.006), and sleep apnea (β=-0.01, SE=0.01, p=0.018). Our results suggest that APOE-ϵ4 is associated with decreased problems in snoring and sleep apnea, in non-demented older adults., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

In the present data, we provide the details of the cross-sectional study, from the Washington Heights-Inwood Community Aging Project (WHICAP) that examined the association between Apolipoprotein E (APOE-ε4) and snoring/sleep apnea. A total of 1944 non-demented older adults constituted our sample. Sleep dysfunction was measured using sleep categories derived from the Medical Outcomes Study Sleep Scale. Stratified analyses were conducted in order to examine the association between APOE-ε4 and sleep variables by ethnic group. For further analyses and enhanced discussion, see "Examining the association between Apolipoprotein E (APOE) and self-reported sleep disturbances in non-demented older adults" by Tsapanou et al. (2015) [1].

Objective: To examine the association between odor identification deficits and future mortality in a multiethnic community cohort of older adults., Methods: Participants were evaluated with the 40-item University of Pennsylvania Smell Identification Test (UPSIT). Follow-up occurred at 2-year intervals with information on death obtained from informant interviews and the National Death Index., Results: During follow-up (mean = 4.1 years, standard deviation = 2.6), 349 of 1,169 (29.9%) participants died. Participants who died were more likely to be older (p < 0.001), be male (p < 0.001), have lower UPSIT scores (p < 0.001), and have a diagnosis of dementia (p < 0.001). In a Cox model, the association between lower UPSIT score and mortality (hazard ratio [HR] = 1.07 per point interval, 95% confidence interval [CI] = 1.05-1.08, p < 0.001) persisted after controlling for age, gender, education, ethnicity, language, modified Charlson medical comorbidity index, dementia, depression, alcohol abuse, head injury, smoking, body mass index, and vision and hearing impairment (HR = 1.05, 95% CI = 1.03-1.07, p < 0.001). Compared to the fourth quartile with the highest UPSIT scores, HRs for mortality for the first, second, and third quartiles of UPSIT scores were 3.81 (95% CI = 2.71-5.34), 1.75 (95% CI = 1.23-2.50), and 1.58 (95% CI = 1.09-2.30), respectively. Participant mortality rate was 45% in the lowest quartile of UPSIT scores (anosmia) and 18% in the highest quartile of UPSIT scores., Interpretation: Impaired odor identification, particularly in the anosmic range, is associated with increased mortality in older adults even after controlling for dementia and medical comorbidity., (© 2015 American Neurological Association.)

Background/aims: To examine the association between self-reported sleep problems and incidence of dementia in community-dwelling elderly people., Methods: 1,041 nondemented participants over 65 years old were examined longitudinally. Sleep problems were estimated using the RAND Medical Outcomes Study Sleep Scale examining sleep disturbance, snoring, sleep short of breath or with a headache, sleep adequacy, and sleep somnolence. Cox regression analysis was used to examine the association between sleep problems and risk for incident dementia. Age, gender, education, ethnicity, APOE-ε4, stroke, heart disease, hypertension, diabetes, and depression were included as covariates., Results: Over 3 years of follow-up, 966 (92.8%) participants remained nondemented, while 78 (7.2%) developed dementia. In unadjusted models, sleep inadequacy ('Get the amount of sleep you need') at the initial visit was associated with increased risk of incident dementia (HR = 1.20; 95% CI 1.02-1.42; p = 0.027). Adjusting for all the covariates, increased risk of incident dementia was still associated with sleep inadequacy (HR = 1.20; 95% CI 1.01-1.42; p = 0.040), as well as with increased daytime sleepiness ('Have trouble staying awake during the day') (HR = 1.24; 95% CI 1.00-1.54; p = 0.047)., Conclusion: Our results suggest that sleep inadequacy and increased daytime sleepiness are risk factors for dementia in older adults, independent of demographic and clinical factors.

Objective: In the largest cohort study of neuropsychological outcomes among HIV-infected women to date, we examined the association between HIV status and cognition in relation to other determinants of cognitive function (aim 1) and the pattern and magnitude of impairment across cognitive outcomes (aim 2)., Methods: From 2009 to 2011, 1,521 (1,019 HIV-infected) participants from the Women's Interagency HIV Study (WIHS) completed a comprehensive neuropsychological test battery. We used multivariable regression on raw test scores for the first aim and normative regression-based analyses (t scores) for the second aim. The design was cross-sectional., Results: The effect sizes for HIV status on cognition were very small, accounting for only 0.05 to 0.09 SD units. The effect of HIV status was smaller than that of years of education, age, race, income, and reading level. In adjusted analyses, HIV-infected women performed worse than uninfected women on verbal learning, delayed recall and recognition, and psychomotor speed and attention. The largest deficit was observed in delayed memory. The association of low reading level with cognition was greater in HIV-infected compared to HIV-uninfected women. HIV biomarkers (CD4 count, history of AIDS-defining illness, viral load) were associated with cognitive dysfunction., Conclusions: The effect of HIV on cognition in women is very small except among women with low reading level or HIV-related comorbidities. Direct comparisons of rates of impairment in well-matched groups of HIV-infected men and women are needed to evaluate possible sex differences in cognition., (© 2014 American Academy of Neurology.)

Objective: To determine the predictive utility of baseline odor identification deficits for future cognitive decline and the diagnosis of Alzheimer disease (AD) dementia., Methods: In a multiethnic community cohort in North Manhattan, NY, 1,037 participants without dementia were evaluated with the 40-item University of Pennsylvania Smell Identification Test (UPSIT). In 757 participants, follow-up occurred at 2 years and 4 years., Results: In logistic regression analyses, lower baseline UPSIT scores were associated with cognitive decline (relative risk 1.067 per point interval; 95% confidence interval [CI] 1.040, 1.095; p < 0.0001), and remained significant (relative risk 1.065 per point interval; 95% CI 1.034, 1.095; p < 0.0001) after including covariates. UPSIT, but not Selective Reminding Test-total immediate recall, predicted cognitive decline in participants without baseline cognitive impairment. During follow-up, 101 participants transitioned to AD dementia. In discrete time survival analyses, lower baseline UPSIT scores were associated with transition to AD dementia (hazard ratio 1.099 per point interval; 95% CI 1.067, 1.131; p < 0.0001), and remained highly significant (hazard ratio 1.072 per point interval; 95% CI 1.036, 1.109; p < 0.0001) after including demographic, cognitive, and functional covariates., Conclusions: Impairment in odor identification was superior to deficits in verbal episodic memory in predicting cognitive decline in cognitively intact participants. The findings support the cross-cultural use of a relatively inexpensive odor identification test as an early biomarker of cognitive decline and AD dementia. Such testing may have the potential to select/stratify patients in treatment trials of cognitively impaired patients or prevention trials in cognitively intact individuals., (© 2014 American Academy of Neurology.)

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.

This review summarizes the findings and importance of 12 articles from research at Columbia University in New York City that were among the most cited in the literature between 2006 and 2011. The 12 articles summarized in this review made important contributions to the field of Alzheimer's disease in the last 5 years. Four of the articles established the Mediterranean diet as a food consumption pattern that may prevent Alzheimer's disease in addition to physical activity. Two of the articles advanced our knowledge of predictors of conversion from mild cognitive impairment to dementia. Four of the articles provided important knowledge of risk factors for the progression of Alzheimer's disease and its complications. Lastly, one of the articles laid the theoretical framework for the study of cognitive reserve, an important modifier of the manifestation of Alzheimer's disease. These studies have advanced our knowledge about risk factors, modifiers, and progression of late onset Alzheimer's disease

Objective: To compare neuropsychological scores in women infected with HIV, women infected with both HIV and hepatitis C, and uninfected subjects., Background: Some, but not all, studies have demonstrated that dual infection with Hepatitis C virus (HCV) and HIV has worse effects on cognition than infection with HIV alone., Design/methods: The Women's Interagency HIV Study is an ongoing prospective study of the natural history of HIV in women where participants are reevaluated every 6 months. In a cross-sectional analysis, we evaluated the effects of active HIV and HCV infections on scores on symbol-digit modalities test, the Stroop interference test, and trails A and B after controlling for age, ethnicity, education, depression, liver disease, and current or past substance abuse., Results: Data were available for 1338 women-17.8 % had detectable hepatitis C virus and 67% were HIV seropositive. In fully adjusted general linear models, HCV viremia was not associated with scores on any of the cognitive tests., Conclusions: In this large sample of women, active HCV infection was not associated with scores on a small battery of neuropsychological tests.

Despite the use of highly active anti-retroviral treatment (HAART), cognitive impairment remains prevalent in HIV. Indeed a recent study suggested that in certain instances, stopping HAART was associated with improved cognitive function (Robertson et al. Neurology 74(16):1260-1266 2010). HAART is occasionally associated with cardiovascular pathology and such pathology may be associated with cognitive impairment. To explore these associations, we assessed the relative contributions of cardiovascular variables such as hypertension and atherosclerosis, of HIV and HAART to cognition. The participants were members of the Women's Interagency HIV Study. In the analysis of cross-sectional data using general linear models, we assessed the relationship between each cardiovascular variable and Stroop interference time and symbol digit modalities test while adjusting for age, HIV, education, depression, and race/ethnicity. We also analyzed the association of summary measures of HAART use with cognition. In multivariate models, significance was limited to carotid lesions and carotid intima-medial thickness quintile (CIMT) with Stroop interference time (for carotid lesions, coefficient = 10.5, CI 3.5 to 17.5, p = 0.003, N = 1,130; for CIMT quintile, coefficient = 8.6, CI = 1.7 to 15.4, p = 0.025, N = 1,130). The summary measures of protease inhibitor use and other HAART measures were in most cases not associated with cognitive score in multivariate models. We conclude that in the HAART era among middle-aged women with HIV, carotid disease may be significantly associated with some measures of cognitive impairment. In this cross-sectional study, we could detect neither positive nor negative effects of HAART on cognition.

Objectives: To cross-sectionally quantify the contribution of proxy measures of cognitive reserve reflective of the lifespan, such as education, socioeconomic status (SES), reading ability, and cognitive activities, in explaining late-life cognition., Design: Prospective observational cohort study of aging., Setting: Retirement communities across the Chicago metropolitan area., Participants: Nine hundred fifty-one older adults free of clinical dementia in the Rush Memory and Aging Project (aged 79 ± 8, 74% female)., Measurements: Baseline data on multiple life course factors included early-, mid-, and late-life participation in cognitive activities; early-life and adult SES; education; and reading ability (National Adult Reading Test; NART). Path analysis quantified direct and indirect standardized effects of life course factors on global cognition and five cognitive domains (episodic memory, semantic memory, working memory, visuospatial ability, perceptual speed)., Results: Adjusting for age, sex, and race, education had the strongest association with global cognition, episodic memory, semantic memory, and visuospatial ability, whereas NART (followed by education) had the strongest association with working memory. Late-life cognitive activities had the strongest association with perceptual speed, followed by education., Conclusions: These cross-sectional findings suggest that education and reading ability are the most-robust proxy measures of cognitive reserve in relation to late-life cognition. Additional research leveraging path analysis is warranted to better understand how these life course factors, reflecting the latent construct of cognitive reserve, affect abnormal cognitive aging., (© 2011, Copyright the Authors. Journal compilation © 2011, The American Geriatrics Society.)

Cognitive reserve, broadly conceived, encompasses aspects of brain structure and function that optimize individual performance in the presence of injury or pathology. Reserve is defined as a feature of brain structure and/or function that modifies the relationship between injury or pathology and performance on neuropsychological tasks or clinical outcomes. Reserve is challenging to study for two reasons. The first is: reserve is a hypothetical construct, and direct measures of reserve are not available. Proxy variables and latent variable models are used to attempt to operationalize reserve. The second is: in vivo measures of neuronal pathology are not widely available. It is challenging to develop and test models involving a risk factor (injury or pathology), a moderator (reserve) and an outcome (performance or clinical status) when neither the risk factor nor the moderator are measured directly. We discuss approaches for quantifying reserve with latent variable models, with emphasis on their application in the analysis of data from observational studies. Increasingly latent variable models are used to generate composites of cognitive reserve based on multiple proxies. We review the theoretical and ontological status of latent variable modeling approaches to cognitive reserve, and suggest research strategies for advancing the field.

The 2008 Diversity Summit recognized the many advantages of increasing the number of neuropsychologists from ethnically diverse backgrounds. The Summit addressed the aspiration of creating a more ethnically diverse body of neuropsychologists by increasing the recruitment of ethnic minority students to neuropsychology training programs. Challenges to successful recruitment and retention of ethnic minority students were discussion points at the Summit. This paper summarizes and expands these points and also suggests solutions to these challenges with the aim of stimulating innovative approaches to increasing the representation of ethnic minorities in neuropsychology.

US demographic and sociopolitical shifts have resulted in a rapidly growing need for culturally competent neuropsychological services. However, clinical neuropsychology as a field has not kept pace with the needs of ethnic minority clients. In this discussion we review: historical precedents and the limits of universalism in neuropsychology; ethical/professional guidelines pertinent to neuropsychological practice with ethnic minority clients; critical cultural considerations in neuropsychology; current disparities germane to practice; and challenges to the provision of services to racial/ethnic minority clients. We provide a call to action for neuropsychologists and related organizations to advance multiculturalism and diversity within the field by increasing multicultural awareness and knowledge, multicultural education and training, multicultural neuropsychological research, and the provision of culturally competent neuropsychological services to racial/ethnic minority clients. Lastly, we discuss strategies for increasing the provision of culturally competent neuropsychological services, and offer several resources to meet these goals.

Background: Hippocampal atrophy and reductions in basal cerebral blood volume (CBV), a hemodynamic correlate of brain function, occur with cognitive impairment in Alzheimer disease, but whether these are early or late changes remains unclear. Magnetic resonance imaging is used to assess structure and function in the hippocampal formation., Objective: To estimate differences in the associations of hippocampal and entorhinal cortex volumes and CBV with memory function in the early and late stages of cognitive impairment by relating these measures to memory function in persons with and without dementia who underwent detailed brain imaging and neuropsychological assessment., Design: Multivariate regression analyses were used to relate entorhinal cortex volume, entorhinal cortex CBV, hippocampal volume, and hippocampal CBV to measurements of memory performance. The same measures were related to language function as a reference cognitive domain., Setting: Community-based cohort., Participants: Two hundred thirty-one elderly Medicare recipients (aged > or =65 years) residing in northern Manhattan, New York., Main Outcome Measures: Values for entorhinal cortex volume, hippocampal volume, entorhinal cortex CBV, and hippocampal CBV and their relation to memory performance., Results: No association was noted between entorhinal cortex volume or hippocampal CBV and memory. Decreased hippocampal volume was strongly associated with worse performance in total recall, and lower entorhinal cortex CBV was associated with lower performance in delayed recall. Excluding persons with Alzheimer disease, the association of entorhinal cortex CBV with memory measures was stronger, whereas the association between hippocampal volume and total recall became nonsignificant., Conclusions: In the early stages of Alzheimer disease or in persons without dementia with worse memory ability, functional and metabolic hippocampal hypofunction contributes to memory impairment, whereas in the later stages, functional and structural changes play a role.

Plasma Abeta42 and Abeta40 levels are putative biomarkers for Alzheimer's disease (AD), but their significance and predictive value have been inconclusive. In AD transgenic models, plasma and cerebrospinal fluid levels of Abeta42 and Abeta40 increase with age but subsequently decrease when Abeta begins to accumulate in brain and with the onset of cognitive impairment. To determine the predictive value of Abeta levels in elderly populations, we investigated how plasma Abeta42, Abeta40, and a protofibrillar subspecies of Abeta42 changed over time and with the onset of cognitive impairment or AD. In a cohort of 1,125 elderly persons without dementia, 104 (9.2%) of the participants developed AD over 4.6 years of follow-up. Higher plasma Abeta42 levels at the onset of the study were associated with a threefold increased risk of AD. However, conversion to AD was accompanied by a significant decline in plasma Abeta42, a decreased Abeta42/Abeta40 ratio and, with the onset of cognitive impairment, decreased protofibrillar Abeta42 levels. Our results suggest individuals with elevated plasma Abeta42 are at increased risk of AD and that with the onset of disease, the decline in some forms of Abeta may reflect compartmentalization of Abeta peptides in the brain.

Background: There are conflicting data relating plasma lipids to the risk of Alzheimer's disease (AD). We explored the association of plasma lipids to mild cognitive impairment (MCI), a transitional stage between normal cognition and dementia, in a prospective community-based cohort study among randomly sampled Medicare recipients > or =65 years. Baseline data were collected from 1992 to 1994, follow-up data were collected at 18-month intervals., Methods: Multivariate proportional hazards regression was used to relate plasma lipid levels to incident total MCI, amnestic MCI and nonamnestic MCI in 854 persons without MCI or dementia at baseline., Results: There were 324 cases of incident MCI, 153 cases of amnestic MCI and 171 cases of nonamnestic MCI during 4,189 person-years of follow-up. Higher levels of total cholesterol and LDL were associated with a decreased risk of total MCI in models adjusting for age and sex. However, these associations were attenuated after adjusting for ethnicity, education, APOEepsilon4 and vascular risk factors. There was no association between lipids and the risk of amnestic or nonamnestic MCI, and there was no effect of lipid-lowering treatment on MCI risk., Conclusions: Plasma lipid levels or lipid-lowering treatment in the elderly are not associated with the risk of MCI., (Copyright 2008 S. Karger AG, Basel.)

Objective: To explore whether hypertension is associated with the risk of mild cognitive impairment (MCI), an intermediate stage of dementia, because there are conflicting data relating hypertension to the risk of Alzheimer disease., Design and Setting: Prospective community-based cohort study conducted in northern Manhattan. Multivariate proportional hazards regression analyses were used, relating hypertension to incident all-cause MCI, amnestic MCI, and nonamnestic MCI in 918 persons without prevalent MCI at baseline followed up for a mean of 4.7 years., Results: There were 334 cases of incident MCI, 160 cases of amnestic MCI, and 174 cases of nonamnestic MCI during 4337 person-years of follow-up. Hypertension was associated with an increased risk of all-cause MCI (hazard ratio, 1.40; 95% confidence interval, 1.06-1.77; P = .02) and nonamnestic MCI (hazard ratio, 1.70; 95% confidence interval, 1.13-2.42; P = .009) after adjusting for age and sex. Both associations were slightly attenuated in models additionally adjusting for stroke and other vascular risk factors. There was no association between hypertension and the risk of amnestic MCI (hazard ratio, 1.10; 95% confidence interval, 0.79-1.63; P = .49). Consistent with this association, hypertension was related with the slope of change in an executive ability score, but not with memory or language score. There was no effect modification of the association between hypertension and MCI by APOEepsilon4 genotype or use of antihypertensive medication., Conclusions: A history of hypertension is related to a higher risk of MCI. The association seems to be stronger with the nonamnestic than the amnestic type of MCI in the elderly. These findings suggest that prevention and treatment of hypertension may have an important impact in lowering the risk of cognitive impairment.

Background: Vascular risk factors increase the risk of Alzheimer's disease (AD). The mechanisms for these associations are unclear, and may be due to misdiagnosis of a vascular dementia syndrome as AD., Objective: To examine differences in neuropsychological profile among persons diagnosed clinically with AD with and without vascular risk factors or stroke., Methods: Community based cohort study. Individual and composite scores of neuropsychological tests at the time of clinical diagnosis of incident AD were compared among 243 persons with and without vascular risk factors or stroke., Results: Among subjects with incident AD, diabetes was associated with lower performance in Delayed Recall of the Selective Reminding Test (SRT), while persons diagnosed with hypertension scored lower in consistent long term recall (CLTR) of the SRT and current smokers scored lower in Category Fluency. None of the risk factors was associated with differences in composite scores in memory, abstract/visuospatial or language domain, nor was the number of risk factors per person. Persons with stroke had a higher delayed recall score at the time of AD diagnosis., Conclusion: The presence of vascular risk factors among persons with clinically diagnosed AD was associated with subtle differences in neuropsychological profile at the time of diagnosis. This study needs to be replicated in samples with brain imaging, a comprehensive executive abilities battery, and pathological diagnosis of AD.

Objective: Despite numerous clinical trials, it is unknown whether ethnicity affects treatment response to cognitive enhancers in Alzheimer's disease (AD). There is convincing evidence of ethnic and genetic variability in drug metabolism. This article reviews the available data on ethnicity in clinical trials for AD to answer two questions: (1) what are the challenges to diagnose and treat AD across different ethnic groups, and (2) are there differences in response to pharmacologic interventions for AD across these different ethnic groups?, Method: Available data from Alzheimer's Disease Cooperative Study (ADCS) randomized controlled clinical trials and from randomized controlled industry-sponsored trials for four cognitive enhancers (donepezil, galantamine, rivastigmine and sabeluzole) were pooled to assess the numbers of non-Caucasian participants., Results: The participation of ethnic minority subjects in clinical trials for AD was dependent on the funding source, although Caucasian participants were over-represented and non-Caucasian participants were under-represented in the clinical trials. Because of the low participation rate of ethnic minorities, there were insufficient data to assess any differences in treatment outcome among different ethnic groups. Strategies to improve diversity in clinical trials are discussed., Conclusion: Greater participation of ethnically diverse participants in clinical trials for AD would generate additional information on possible differences in metabolism, treatment response, adverse events to therapeutic agents, and could foster the investigation of genetic variability among ethnic groups.

Objective: To investigate the association between Alzheimer disease (AD) and variant alleles in SORL1 using a series of single nucleotide polymorphisms (SNPs) in an urban, multiethnic, community-based population., Design: We used a nested case-control analysis in a population-based, prospective study of aging and dementia in Medicare recipients, 65 years and older., Setting: Northern Manhattan, NY., Participants: There were 296 patients with probable AD and 428 healthy, elderly controls. The participants were African American (34%), Caribbean Hispanic (51%), or non-Hispanic white (15%)., Main Outcome Measures: We genotyped all 29 SNPs in SORL1 that were examined in the earlier report. We assessed allelic association with AD using standard case-control methods, which included apolipoprotein E genotype as a covariate., Results: Several individual SNPs and SNP haplotypes were significantly associated with AD in this prospectively collected community-based cohort, confirming the previously reported positive association of SORL1 with AD. Single nucleotide polymorphism 12, near the 5' region, was associated with AD in African American and Hispanic individuals. Two SNPs in the 3' region were also associated with AD in African American (SNP 26) and non-Hispanic white (SNP 20) individuals. A single haplotype in the 3' region was associated with AD in Hispanic individuals. However, several different haplotypes were associated with AD in African American and white individuals, including the TTC haplotypes at SNPs 23 through 25 (P = .035), which was significantly associated with AD in the North European white individuals in our previous report., Conclusions: This study confirms the association between genetic variants in SORL1 and AD. While the associations observed in these data sets overlap with those previously reported, the finding of novel SNP and haplotype associations suggests that there may be extensive allelic heterogeneity in SORL1. Broad regions of the SORL1 gene will therefore need to be scrutinized for functional pathogenic variants.

A critical focus of neuropsychological research is to identify unbiased ways to compare heterogeneous groups on background variables relevant to neuropsychological performance. Whereas recent work has pointed to single word reading as a less culturally biased measure of educational experience than years of education, the extent to which reading score captures a broad range of educational experience and does so consistently across ethnic and language groups is unknown. The current study evaluated reading in relation to years of education in English-speaking Whites, Blacks, and Hispanics, and Spanish-speaking Hispanic older persons (n = 342). Consistent with previous work, reading scores at each grade level were lower in English speaking ethnic minorities than in Whites, supporting the idea that variables related to lifetime educational experience are often confounded with ethnicity. Standardized reading scores were highest in the Spanish speakers; however, interpretation of this difference is limited because scores were necessarily derived using separate normative samples. Importantly, the slopes of reading score by years of education were comparable across all groups. That is, reading scores rose consistently with years of education independently of ethnicity or language, suggesting that such scores can be treated comparably for theoretical and statistical purposes in multiethnic and multilingual samples.