The neuropathological landscape of small vessel disease and Lewy pathology in a cohort of Hispanic and non-Hispanic White decedents with Alzheimer disease.

Cerebrovascular and α-synuclein pathologies are frequently observed alongside Alzheimer disease (AD). The heterogeneity of AD necessitates comprehensive approaches to postmortem studies, including the representation of historically underrepresented ethnic groups. In this cohort study, we evaluated small vessel disease pathologies and α-synuclein deposits among Hispanic decedents (HD, n = 92) and non-Hispanic White decedents (NHWD, n = 184) from three Alzheimer's Disease Research Centers: Columbia University, University of California San Diego, and University of California Davis. The study included cases with a pathological diagnosis of Intermediate/High AD based on the National Institute on Aging- Alzheimer's Association (NIA-AA) and/or NIA-Reagan criteria. A 2:1 random comparison sample of NHWD was frequency-balanced and matched with HD by age and sex. An expert blinded to demographics and center origin evaluated arteriolosclerosis, cerebral amyloid angiopathy (CAA), and Lewy bodies/Lewy neurites (LBs/LNs) with a semi-quantitative approach using established criteria. There were many similarities and a few differences among groups. HD showed more severe Vonsattel grading of CAA in the cerebellum (p = 0.04), higher CAA density in the posterior hippocampus and cerebellum (ps = 0.01), and increased LBs/LNs density in the frontal (p = 0.01) and temporal cortices (p = 0.03), as determined by Wilcoxon's test. Ordinal logistic regression adjusting for age, sex, and center confirmed these findings except for LBs/LNs in the temporal cortex. Results indicate HD with AD exhibit greater CAA and α-synuclein burdens in select neuroanatomic regions when compared to age- and sex-matched NHWD with AD. These findings aid in the generalizability of concurrent arteriolosclerosis, CAA, and LBs/LNs topography and severity within the setting of pathologically confirmed AD, particularly in persons of Hispanic descent, showing many similarities and a few differences to those of NHW descent and providing insights into precision medicine approaches.

Disparities in Metabolic Syndrome and Neurocognitive Function Among Older Hispanics/Latinos with Human Immunodeficiency Virus.

Neurocognitive impairment and metabolic syndrome (MetS) are prevalent in persons with HIV (PWH). We examined disparities in HIV-associated neurocognitive function between Hispanic and non-Hispanic White older PWH, and the role of MetS in explaining these disparities. Participants included 116 community-dwelling PWH aged 50-75 years enrolled in a cohort study in southern California [58 Hispanic (53% Spanish speaking) and 58 age-comparable non-Hispanic White; overall group: age: M = 57.9, standard deviation (SD) = 5.7; education (years): M = 13, SD = 3.4; 83% male, 58% AIDS, 94% on antiretroviral therapy]. Global neurocognition was derived from T-scores adjusted for demographics (age, education, sex, ethnicity, language) on a battery of 10 cognitive tests. MetS was ascertained via standard criteria that considered central obesity, and fasting elevated triglycerides, low high-density lipoprotein cholesterol and elevated glucose, or medical treatment for these conditions. Covariates examined included sociodemographic, psychiatric, substance use and HIV disease characteristics. Compared with non-Hispanic Whites, Hispanics showed worse global neurocognitive function (Cohen's d = 0.56, p < 0.05) and had higher rates of MetS (38% vs. 56%, p < 0.05). A stepwise regression model including ethnicity and significant covariates showed Hispanic ethnicity was the sole significant predictor of worse global neurocognition (B = -3.82, SE = 1.27, p < 0.01). A model also including MetS showed that both Hispanic ethnicity (B = -3.39, SE = 1.31, p = 0.01) and MetS (B = -2.73, SE = 1.31, p = 0.04) were independently associated with worse neurocognition. In conclusion, findings indicate that increased MetS is associated with worse neurocognitive function in both Hispanic and non-Hispanic White older PWH, but does not explain neurocognitive disparities. MetS remains an important target for intervention efforts to ameliorate neurocognitive dysfunction among diverse older PWH.

The Association Between Physical Activity and Cognition in a Racially/Ethnically Diverse Cohort of Older Adults: Results From the Kaiser Healthy Aging and Diverse Life Experiences Study.

OBJECTIVE: Most prior research on physical activity (PA) and cognition is based on predominantly white cohorts and focused on associations of PA with mean (average) cognition versus the distribution of cognition. Quantile regression offers a novel way to quantify how PA affects cognition across the entire distribution. METHODS: The Kaiser Healthy Aging and Diverse Life Experiences study includes 30% white, 19% black, 25% Asian, and 26% Latinx adults age 65+ living in Northern California (n = 1600). The frequency of light or heavy PA was summarized as 2 continuous variables. Outcomes were z-scored executive function, semantic memory, and verbal episodic memory. We tested associations of PA with mean cognition using linear regression and used quantile regression to estimate the association of PA with the 10th-90th percentiles of cognitive scores. RESULTS: Higher levels of PA were associated with higher mean semantic memory (b = 0.10; 95% CI: 0.06, 0.14) and executive function (b = 0.05; 95% CI: 0.01, 0.09). Associations of PA across all 3 cognitive domains were stronger at low quantiles of cognition. CONCLUSION: PA is associated with cognition in this racially/ethnically diverse sample and may have larger benefits for individuals with low cognitive scores, who are most vulnerable to dementia.

Evaluation of racial and ethnic heterogeneity in the associations of sleep quality and sleep apnea risk with cognitive function and cognitive decline.

INTRODUCTION: The prevalence of poor sleep quality and sleep apnea differs by race and ethnicity and may contribute to racial disparities in cognitive aging. We investigated whether sleep quality and sleep apnea risk were associated with cognitive function and decline and whether the associations differed by race/ethnicity. METHODS: Participants from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE; N = 1690; mean age: 75.7 years) study, a cohort of Asian, Black, Latino, and White participants, completed a modified Pittsburgh Sleep Quality Index assessing subjective sleep quality, latency, duration, disturbances, sleep medication use, and daytime dysfunction. Sleep apnea risk was measured by questions about snoring, tiredness, and whether apnea was observed. Executive function and verbal episodic memory were assessed at three time points over an average of 2.7 years with the Spanish and English Neuropsychological Assessment Scale. We fit linear mixed-effect models and stratified analyses by race/ethnicity. RESULTS: Higher sleep apnea risk was associated with faster declines in verbal episodic memory (ß^ sleep apnea = -0.02, 95% confidence interval [CI], -0.04, -0.001) but not in executive function. Poorer sleep quality was associated with lower levels of and faster decline in executive function but not in verbal episodic memory. Race/ethnicity modified these associations: compared to estimated effects among White participants, poorer global sleep quality (ß^ sleep*time = -0.02, 95% CI, -0.02, -0.01) was associated with larger effects on decline in executive function among Black participants. Estimated effects of some individual sleep quality components were also modified by race/ethnicity; for example, sleep medication use was associated with faster declines in executive function (ß^ sleep*time = -0.05, 95% CI, -0.07, -0.03) and verbal episodic memory ß^ sleep*time = -0.04, 95% CI, -0.07, -0.02) among Black participants compared to White participants. DISCUSSION: Observational evidence indicates sleep quality is a promising target for addressing racial/ethnic disparities in cognitive aging, especially among Black older adults. Highlights: Sleep apnea risk was associated with faster declines in verbal episodic memory but not executive function among all participants.Global sleep quality was associated with lower levels of and faster decline in executive function but not verbal episodic memory among all participants.Black older adults were particularly susceptible to the estimated adverse cognitive impacts of global sleep quality, particularly the use of sleep medication.

Associations between personality and psychological characteristics and cognitive outcomes among older adults.

Prior research has shown that some personality traits are associated with cognitive outcomes and may confirm risk or protection against cognitive decline. The present study expands on previous work to examine the association between a more comprehensive set of psychological characteristics and cognitive performance in a diverse cohort of older adults. We also examine whether controlling for brain atrophy influences the association between psychological characteristics and cognitive function. A total of 157 older adults completed a battery of psychological questionnaires (Openness to Experience, Conscientiousness, Agreeableness, Neuroticism, Extraversion, positive affect, negative affect-sadness, negative affect-anger, sense of purpose, loneliness, grit, and self-efficacy). Cognitive outcomes were measured across multiple domains: episodic memory, semantic memory, executive function, and spatial ability. Baseline brain (MRI) variables included gray matter, hippocampus, and total white matter hyperintensity volume. Parallel process, multilevel models yielded intercept (individual cognitive domain scores) and linear slope (global cognitive change) random effects for the cognitive outcomes. Positive affect (ß = 0.013, SE = 0.005, p = .004) and Openness (ß = 0.018, SE = 0.007, p = .009) were associated with less cognitive change, independent of baseline brain variables and covariates. Greater sadness predicted more cognitive decline when controlling for covariates, but not brain atrophy. A variety of psychological characteristics were associated with the cross-sectional measures of cognition. This study highlights the important impact of positive and negative affect on reducing or enhancing the risk of longitudinal cognitive decline. Such findings are especially important, given the available efficacious interventions that can improve affect. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Timing and level of educational attainment and late-life cognition in the KHANDLE study.

INTRODUCTION: The timing of educational attainment may modify its effects on late-life cognition, yet most studies evaluate education only at a single time point. METHODS: Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study cohort participants (N = 554) reported educational attainment (dichotomized at any college education) at two time points, and we classified them as having low, high, or later-life high educational attainment. Linear mixed-effects models estimated associations between educational attainment change groups and domain-specific cognitive outcomes (z-standardized). RESULTS: Compared to low educational attainment, high (ß= 0.59 SD units; 95% confidence interval [CI]: 0.39, 0.79) and later-life high educational attainment (ß = 0.22; 95% CI: 0.00, 0.44) were associated with higher executive function. Only high educational attainment was associated with higher verbal episodic memory (ß = 0.27; 95% CI: 0.06, 0.48). DISCUSSION: Level and timing of educational attainment are both associated with domain-specific cognition. A single assessment for educational attainment may inadequately characterize protective associations with late-life cognition. HIGHLIGHTS: Few studies have examined both level and timing of educational attainment on cognition. Marginalized populations are more likely to attain higher education in adulthood. Higher educational attainment in late life is also associated with higher cognition.

Self-reported mid- to late-life physical and recreational activities: Associations with late-life cognition.

OBJECTIVE: Physical and recreational activities are behaviors that may modify risk of late-life cognitive decline. We sought to examine the role of retrospectively self-reported midlife (age 40) physical and recreational activity engagement - and self-reported change in these activities from age 40 to initial study visit - in predicting late-life cognition. METHOD: Data were obtained from 898 participants in a longitudinal study of cognitive aging in demographically and cognitively diverse older adults (Age: range = 49-93 years, M = 75, SD = 7.19). Self-reported physical and recreational activity participation at age 40 and at the initial study visit were quantified using the Life Experiences Assessment Form. Change in activities was modeled using latent change scores. Cognitive outcomes were obtained annually (range = 2-17 years) using the Spanish and English Neuropsychological Assessment Scales, which measure verbal episodic memory, semantic memory, visuospatial processing, and executive functioning. RESULTS: Physical activity engagement at age 40 was strongly associated with cognitive performance in all four domains at the initial visit and with global cognitive slope. However, change in physical activities after age 40 was not associated with cognitive outcomes. In contrast, recreational activity engagement - both at age 40 and change after 40 - was predictive of cognitive intercepts and slope. CONCLUSIONS: Retrospectively self-reported midlife physical and recreational activity engagement were strongly associated with late-life cognition - both level of performance and rate of future decline. However, the data suggest that maintenance of recreational activity engagement (e.g., writing, taking classes, reading) after age 40 is more strongly associated with late-life cognition than continued maintenance of physical activity levels.

What is the association between adverse childhood experiences and late-life cognitive decline? Study of Healthy Aging in African Americans (STAR) cohort study.

OBJECTIVES: Adverse childhood experiences (ACEs) are associated with higher risk of chronic disease, but little is known about the association with late life cognitive decline. We examined the longitudinal association between ACEs and late-life cognitive decline in the Study of Healthy Aging in African Americans (STAR). DESIGN: Linear mixed models with random intercepts and slope examined the association of individual and composite ACEs with cognitive change adjusting for years from baseline (timescale), baseline age, sex, parental education, childhood socioeconomic status and childhood social support. Participants reported whether they had experienced nine types of ACEs. Executive function and verbal episodic memory were measured up to three times over a 3-year period using the Spanish and English Neuropsychological Assessment Scales. SETTINGS: Kaiser Permanente Northern California members living in the Bay Area. PARTICIPANTS: STAR is a cohort study of cognitive ageing launched in 2018 that has enrolled 764 black Americans ages ≥50 years (mean age=67.5; SD=8.5). RESULTS: Twenty-one per cent of participants reported no ACEs, 24% one ACE, 20% two ACEs, 17% three ACEs and 17% four or more ACEs. Compared with no ACEs, two ACEs (ß=0.117; 95% CI 0.052 to 0.182), three ACEs (ß=0.075; 95% CI 0.007 to 0.143) and four or more ACEs (ß=0.089; 95% CI 0.002 to 0.158) were associated with less decline in executive function. There were no significant associations between number of ACEs and baseline or longitudinal verbal episodic memory or between individual ACEs and executive function or verbal episodic memory. CONCLUSION: In this cohort of older black Americans, there was no association between ACEs and baseline cognition or cognitive change in verbal episodic memory; however, experiencing ≥ 2 ACEs was associated with less decline in executive function. These results may indicate that participants who survived to age 50+ and experienced ACEs may have cognitive resilience that warrants further investigation.

Measurement precision across cognitive domains in the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set.

OBJECTIVE: To demonstrate measurement precision of cognitive domains in the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set. METHOD: Participants with normal cognition (NC), mild cognitive impairment (MCI), and Alzheimer's disease (AD) were included from all ADNI waves. We used data from each person's last study visit to calibrate scores for memory, executive function, language, and visuospatial functioning. We extracted item information functions for each domain and used these to calculate standard errors of measurement. We derived scores for each domain for each diagnostic group and plotted standard errors of measurement for the observed range of scores. RESULTS: Across all waves, there were 961 people with NC, 825 people with MCI, and 694 people with AD at their most recent study visit (data pulled February 25, 2019). Across ADNI's battery there were 34 memory items, 18 executive function items, 20 language items, and seven visuospatial items. Scores for each domain were highest on average for people with NC, intermediate for people with MCI, and lowest for people with AD, with most scores across all groups in the range of -1 to +1. Standard error of measurement in the range from -1 to +1 was highest for memory, intermediate for language and executive functioning, and lowest for visuospatial. CONCLUSION: Modern psychometric approaches provide tools to help understand measurement precision of the scales used in studies. In ADNI, there are important differences in measurement precision across cognitive domains. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Harmonization of cognitive screening tools for dementia across diverse samples: A simulation study.

Introduction: Research focusing on cognitive aging and dementia is a global endeavor. However, cross-national differences in cognition are embedded in other sociocultural differences, precluding direct comparisons of test scores. Such comparisons can be facilitated by co-calibration using item response theory (IRT). The goal of this study was to explore, using simulation, the necessary conditions for accurate harmonization of cognitive data. Method: Neuropsychological test scores from the US Health and Retirement Study (HRS) and the Mexican Health and Aging Study (MHAS) were subjected to IRT analysis to estimate item parameters and sample means and standard deviations. These estimates were used to generate simulated item response patterns under 10 scenarios that adjusted the quality and quantity of linking items used in harmonization. IRT-derived factor scores were compared to the known population values to assess bias, efficiency, accuracy, and reliability of the harmonized data. Results: The current configuration of HRS and MHAS data was not suitable for harmonization, as poor linking item quality led to large bias in both cohorts. Scenarios with more numerous and higher quality linking items led to less biased and more accurate harmonization. Discussion: Linking items must possess low measurement error across the range of latent ability for co-calibration to be successful. HIGHLIGHTS: We developed a statistical simulation platform to evaluate the degree to which cross-sample harmonization accuracy varies as a function of the quality and quantity of linking items.Two large studies of aging-one in Mexico and one in the United States-use three common items to measure cognition.These three common items have weak correspondence with the ability being measured and are all low in difficulty.Harmonized scores derived from the three common linking items will provide biased and inaccurate estimates of cognitive ability.Harmonization accuracy is greatest when linking items vary in difficulty and are strongly related to the ability being measured.

Pragmatic approaches to handling practice effects in longitudinal cognitive aging research.

INTRODUCTION: The challenge of accounting for practice effects (PEs) when modeling cognitive change was amplified by the COVID-19 pandemic, which introduced period and mode effects that may bias the estimation of cognitive trajectory. METHODS: In three Kaiser Permanente Northern California prospective cohorts, we compared predicted cognitive trajectories and the association of grip strength with cognitive decline using three approaches: (1) no acknowledgment of PE, (2) inclusion of a wave indicator, and (3) constraining PE based on a preliminary model (APM) fit using a subset of the data. RESULTS: APM-based correction for PEs based on balanced, pre-pandemic data, and with current age as the timescale produced the smallest discrepancy between within-person and between-person estimated age effects. Estimated associations between grip strength and cognitive decline were not sensitive to the approach used. DISCUSSION: Constraining PEs based on a preliminary model is a flexible, pragmatic approach allowing for meaningful interpretation of cognitive change. HIGHLIGHTS: The magnitude of practice effects (PEs) varied widely by study. When PEs were present, the three PE approaches resulted in divergent estimated age-related cognitive trajectories. Estimated age-related cognitive trajectories were sometimes implausible in models that did not account for PEs. The associations between grip strength and cognitive decline did not differ by the PE approach used. Constraining PEs based on estimates from a preliminary model allows for a meaningful interpretation of cognitive change.

Association of Early Adulthood Hypertension and Blood Pressure Change With Late-Life Neuroimaging Biomarkers.

Importance: The association between hypertension developed before midlife and late-life brain health is understudied and, because of the cardioprotective benefits of estrogen before menopause, may differ by sex. Objective: To assess the association of early adulthood hypertension and blood pressure (BP) change with late-life neuroimaging biomarkers and examine potential sex differences. Design, Setting, and Participants: This cohort study used data from the Study of Healthy Aging in African Americans (STAR) and Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study, which were harmonized longitudinal cohorts of racially and ethnically diverse adults aged 50 years and older from the San Francisco Bay area and Sacramento Valley in California. The STAR was conducted from November 6, 2017, to November 5, 2021, and the KHANDLE study was conducted from April 27, 2017, to June 15, 2021. The current study included 427 participants from the KHANDLE and STAR studies who received health assessments between June 1, 1964, and March 31, 1985. Regional brain volumes and white matter (WM) integrity were measured via magnetic resonance imaging between June 1, 2017, and March 1, 2022. Exposures: Hypertension status (normotension, transition to hypertension, and hypertension) and BP change (last measure minus first measure) were assessed at 2 multiphasic health checkups (MHCs; 1964-1985) in early adulthood (ages 30-40 years). Main Outcomes and Measures: Regional brain volumes and WM integrity were measured using 3T magnetic resonance imaging and z standardized. General linear models adjusted for potential confounders (demographic characteristics and study [KHANDLE or STAR]) were used to assess the association of hypertension and BP change with neuroimaging biomarkers. Sex interactions were tested. Results: Among 427 participants, median (SD) ages were 28.9 (7.3) years at the first MHC, 40.3 (9.4) years at the last MHC, and 74.8 (8.0) years at neuroimaging. A total of 263 participants (61.6%) were female and 231 (54.1%) were Black. Overall, 191 participants (44.7%) had normotension, 68 (15.9%) transitioned to hypertension, and 168 (39.3%) had hypertension. Compared with participants who had normotension, those who had hypertension and those who transitioned to hypertension had smaller cerebral volumes (hypertension: ß = -0.26 [95% CI, -0.41 to -0.10]; transition to hypertension: ß = -0.23 [95% CI, -0.44 to -0.23]), with similar differences in cerebral gray matter volume (hypertension: ß = -0.32 [95% CI, -0.52 to -0.13]; transition to hypertension: ß = -0.30 [95% CI, -0.56 to -0.05]), frontal cortex volume (hypertension: ß = -0.43 [95% CI, -0.63 to -0.23]; transition to hypertension: ß = -0.27 [95% CI, -0.53 to 0]), and parietal cortex volume (hypertension: ß = -0.22 [95% CI, -0.42 to -0.02]; transition to hypertension: ß = -0.29 [95% CI, -0.56 to -0.02]). Participants with hypertension also had smaller hippocampal volume (ß = -0.22; 95% CI, -0.42 to -0.02), greater ventricular volumes (lateral ventricle: ß = 0.44 [95% CI, 0.25-0.63]; third ventricle: ß = 0.20 [95% CI, 0.01-0.39]), larger free water volume (ß = 0.35; 95% CI, 0.18-0.52), and lower fractional anisotropy (ß = -0.26; 95% CI, -0.45 to -0.08) than those who had normotension. Holding hypertension status constant, a 5-mm Hg increase in systolic BP was associated with smaller temporal cortex volume (ß = -0.03; 95% CI, -0.06 to -0.01), while a 5-mm Hg increase in diastolic BP was associated with smaller parietal cortex volume (ß = -0.06; 95% CI, -0.10 to -0.02). The negative association of hypertension and BP change with regional brain volumes appeared stronger in men than women for some regions. Conclusions and Relevance: In this cohort study, early adulthood hypertension and BP change were associated with late-life volumetric and WM differences implicated in neurodegeneration and dementia. Sex differences were observed for some brain regions whereby hypertension and increasing BP appeared more detrimental for men. These findings suggest that prevention and treatment of hypertension in early adulthood is important for late-life brain health, particularly among men.

Association of primary lifetime occupational cognitive complexity and cognitive decline in a diverse cohort: Results from the KHANDLE study.

INTRODUCTION: Higher occupational complexity has been linked to favorable cognitive outcomes, but rarely examined in racially and ethnically diverse populations. METHODS: In a diverse cohort (n = 1536), linear mixed-effects models estimated associations between main lifetime occupational complexity and domain-specific cognitive decline (z-standardized). Occupational complexity with data, people, and things were classified using the Dictionary of Occupational Titles. RESULTS: For occupational complexity with data, highest tertile (vs. lowest) was associated with higher baseline executive function (ß = 0.11; 95% confidence interval [CI] 0.00-0.22) and slower annual rate of decline (ß = 0.03; 95% CI 0.01-0.06), and higher baseline semantic memory (ß = 0.14; 95% CI 0.04-0.25). Highest tertile of occupational complexity with people was associated with higher baseline executive function (ß = 0.29; 95% CI 0.18-0.40), verbal episodic memory (ß = 0.12; 95% CI 0.00-0.24), and semantic memory (ß = 0.23; 95% CI 0.12-0.34). DISCUSSION: In a diverse cohort, higher occupational complexity is associated with better cognition. Findings should be verified in larger cohorts. HIGHLIGHT: Few studies have examined associations of occupational complexity with cognition in diverse populations. Racial and ethnic minorities are disproportionately exposed to lower occupational complexity. Occupational complexity with data and people are associated with better cognition.

An empirical measure of resilience explains individual differences in the effect of tau pathology on memory change in aging.

Accurately measuring resilience to preclinical Alzheimer's disease (AD) pathology is essential to understanding an important source of variability in cognitive aging. In a cohort of cognitively normal older adults (n = 123, age 76.75 ± 6.15 yr), we built a multifactorial measure of resilience which moderated the effect of AD pathology on longitudinal cognitive change. Linear residuals-based measures of resilience, along with other proxy measures (education and vocabulary), were entered into a hierarchical partial least-squares path model defining a putative consolidated resilience latent factor (model goodness of fit = 0.77). In a set of validation analyses using linear mixed models predicting longitudinal cognitive change, there was a significant three-way interaction among consolidated resilience, tau and time on episodic memory change (P = 0.001) such that higher resilience blunted the effect of tau pathology on episodic memory decline. Interactions between consolidated resilience and amyloid pathology on non-memory cognition decline suggested that resilience moderates pathology-specific effects on different cognitive domains.

Effects of early-life environment and adulthood SES on cognitive change in a multiethnic cohort.

OBJECTIVES: Early-life socioeconomic status (SES) and adversity are associated with late-life cognition and risk of dementia. We examined the association between early-life SES and adversity and late-life cross-sectional cognitive outcomes as well as global cognitive decline, hypothesizing that adulthood SES would mediate these associations. METHODS: Our sample (N = 837) was a racially and ethnically diverse cohort of non-Hispanic/Latino White (48%), Black (27%), and Hispanic/Latino (19%) participants from Northern California. Participant addresses were geocoded to the level of the census tract, and US Census Tract 2010 variables (e.g., percent with high school diploma) were extracted and combined to create a neighborhood SES composite. We used multilevel latent variable models to estimate early-life (e.g., parental education, whether participant ever went hungry) and adult (participant's education, main occupation) SES factors and their associations with cross-sectional and longitudinal cognitive outcomes of episodic memory, semantic memory, executive function, and spatial ability. RESULTS: Child and adult factors were strongly related to domain-specific cognitive intercepts (0.20-0.48 SD per SD of SES factor); in contrast, SES factors were not related to global cognitive change (0.001-0.01 SD per year per SD of SES factor). Adulthood SES mediated a large percentage (68-75%) of the total early-life effect on cognition. CONCLUSIONS: Early-life sociocontextual factors are more strongly associated with cross-sectional late-life cognitive performance compared to cognitive change; this effect is largely mediated through associations with adulthood SES.

Assessing cognitive impairment in an ethnically diverse cohort of oldest-old: the life after 90 study.

BACKGROUND: Though dementia rates vary by racial or ethnic groups, it is unknown if these disparities remain among those aged 90 or older. AIMS: To test this hypothesis, we used baseline clinical evaluation of 541 ethnically and racially diverse individuals participating in the LifeAfter90 Study to assess how associations between core demographic characteristics and measures of physical and cognitive performance differ across the racial/ethnic groups. METHODS: Participants in this study were long-term non-demented members of Kaiser Permanente Northern California. They were clinically evaluated and diagnosed with normal or impaired cognition (mild cognitive impairment and dementia) through an in-person comprehensive clinical assessment consisting of a detailed medical history, physical and neurological examination, functional, and cognitive tests. RESULTS: The average age at enrollment was 93.0 ± 2.6 years, 62.4% female and 34.2% non-Hispanic White. At initial evaluation 301 participants had normal cognition and 165 had mild cognitive impairment (MCI) and despite screening, 69 participants were determined to have dementia. Age, education, 3MS, FAQ and CDR scores were significantly associated with cognitive impairment (normal versus MCI and dementia), but not gender. There was a significant univariate association between race/ethnicity and cognitive impairment (p < 0.02) being highest among Black (57.4%) and lowest among Asian (32.7%) individuals. After adjustment for age, gender, and education, however, prevalence of cognitive impairment was not influenced by race or ethnicity. CONCLUSION: Our results confirm the ability to reliably assess clinical diagnosis in a diverse sample of very old individuals.

Toward a statistical validation of brain signatures as robust measures of behavioral substrates.

The "brain signature of cognition" concept has garnered interest as a data-driven, exploratory approach to better understand key brain regions involved in specific cognitive functions, with the potential to maximally characterize brain substrates of behavioral outcomes. Previously we presented a method for computing signatures of episodic memory. However, to be a robust brain measure, the signature approach requires a rigorous validation of model performance across a variety of cohorts. Here we report validation results and provide an example of extending it to a second behavioral domain. In each of two discovery data cohorts, we derived regional brain gray matter thickness associations for two domains: neuropsychological and everyday cognition memory. We computed regional association to outcome in 40 randomly selected discovery subsets of size 400 in each cohort. We generated spatial overlap frequency maps and defined high-frequency regions as "consensus" signature masks. Using separate validation datasets, we evaluated replicability of cohort-based consensus model fits and explanatory power by comparing signature model fits with each other and with competing theory-based models. Spatial replications produced convergent consensus signature regions. Consensus signature model fits were highly correlated in 50 random subsets of each validation cohort, indicating high replicability. In comparisons over each full cohort, signature models outperformed other models. In this validation study, we produced signature models that replicated model fits to outcome and outperformed other commonly used measures. Signatures in two memory domains suggested strongly shared brain substrates. Robust brain signatures may therefore be achievable, yielding reliable and useful measures for modeling substrates of behavioral domains.

Evaluating interpersonal discrimination and depressive symptoms as partial mediators of the effects of education on cognition: Evidence from the Study of Healthy Aging in African Americans (STAR).

INTRODUCTION: Education is correlated with positive health outcomes, but associations are sometimes weaker among African Americans. The extent to which exposure to discrimination and depressive symptoms attenuates the education-cognition link has not been investigated. METHODS: Study of Healthy Aging in African Americans (STAR) participants (n = 764; average age 69 years) completed the Spanish and English Neuropsychological Assessment Scales. We assessed everyday and major lifetime discrimination and depressive symptoms as mediators of education effects on cognition using G-estimation with measurement error corrections. RESULTS: Education was correlated with greater major lifetime and everyday discrimination but lower depressive symptoms. Accounting for discrimination and depressive symptoms slightly reduced the estimated effect of education on cognition. The estimated total effect of graduate education (vs 

TDP-43 Pathology in the Setting of Intermediate and High Alzheimer's Disease Neuropathologic Changes: A Preliminary Evaluation Across Ethnoracial Groups.

BACKGROUND: Transactive Response DNA Binding Protein 43 kDa (TDP-43) pathology is frequently found in cases with Alzheimer's disease (AD). TDP-43 pathology is associated with hippocampal atrophy and greater AD severity denoted by cognition and clinical representation. Current TDP-43 pathology studies are predominantly based on non-Hispanic White cohorts. OBJECTIVE: We sought to evaluate the presence of TDP-43 pathology across ethnoracial groups utilizing the National Alzheimer's Coordinating Center; a database containing data from over 29 institutions across the United States. Cases (N = 1135: Hispanics/Latinos = 29, African Americans/Black Americans = 51, Asians/Asian Americans = 10, American Indians/Alaskan Natives = 2, non-Hispanic White = 1043) with intermediate/high AD having data on TDP-43 pathology in the amygdala, hippocampus, entorhinal cortex, and neocortex were included. METHODS: TDP-43 pathology frequency in each neuroanatomic region among ethnoracial groups were compared using generalized linear mixed effects models with center as a random effect adjusting for age at death, education, and gender. RESULTS: Although groups were imbalanced, there was no significant difference across ethnoracial groups based on TDP-43 pathology (p = 0.84). With respect to neuroanatomical regions evaluated, there were no significant differences across ethnoracial groups (p-values > 0.06). There were also no significant differences for age at death and gender ratios across ethnoracial groups based on TDP-43 pathology. Although not statistically significant, TDP-43 pathology was present less often in Hispanic/Latinos (34%) when compared to non-Hispanic Whites (46%). CONCLUSION: While this is a preliminary evaluation, it highlights the need for diverse cohorts and on TDP-43 pathology research across ethnoracial groups. This is the first study to our knowledge having a focus on the neuroanatomical distribution of TDP-43 deposits in Hispanic/Latino decedents with AD.

Generation and age of immigration on later life cognitive performance in KHANDLE.

OBJECTIVES: We examined the association of generational status and age at immigration with later life cognitive outcomes in a diverse sample of Latinos and Asian Americans. DESIGN: Baseline data were obtained from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study, and a prospective cohort is initiated in 2017. SETTING: Older adults in Northern California. PARTICIPANTS: Our cohort consisted of Asians (n = 411) and Latinos (n = 340) who were on average 76 years old (SD = 6.8). MEASUREMENTS: We used multivariable linear regression models to estimate associations between generational status and age at immigration (collapsed into one five-level variable) with measures of verbal episodic memory, semantic memory, and executive function, adjusting for age, gender, race and ethnicity, and own- and parental education. RESULTS: Generational status and age at immigration were associated with cognitive outcomes in a graded manner. Compared to third-generation or higher immigrants, first-generation immigration in adulthood was associated with lower semantic memory (ß = -0.96; 95% CI: -1.12, -0.81) than immigration in adolescence (ß = -0.68; 95% CI: -0.96, -0.41) or childhood (ß = -0.28; 95% CI: -0.49, -0.06). Moreover, immigration in adulthood was associated with lower executive function (ß = -0.63; 95% CI: -0.78, -0.48) than immigration in adolescence (ß = -0.49; 95% CI: -0.75, -0.23). Similarly, compared to third-generation individuals, first-generation immigrants had lower executive functioning scores. CONCLUSIONS: Our study supports the notion that sociocontextual influences in early life impact later life cognitive scores. Longitudinal studies are needed to further clarify how immigration characteristics affect cognitive decline.