Loneliness, cerebrovascular and Alzheimer's disease pathology, and cognition.

INTRODUCTION: Loneliness has a rising public health impact, but research involving neuropathology and representative cohorts has been limited. METHODS: Inverse odds of selection weights were generalized from the autopsy sample of Rush Alzheimer's Disease Center cohorts (N = 680; 89 ± 9 years old; 25% dementia) to the US-representative Health and Retirement Study (N = 8469; 76 ± 7 years old; 5% dementia) to extend external validity. Regressions tested cross-sectional associations between loneliness and (1) Alzheimer's disease (AD) and cerebrovascular pathology; (2) five cognitive domains; and (3) relationships between pathology and cognition, adjusting for depression. RESULTS: In weighted models, greater loneliness was associated with microinfarcts, lower episodic and working memory in the absence of AD pathology, lower working memory in the absence of infarcts, a stronger association of infarcts with lower episodic memory, and a stronger association of microinfarcts with lower working and semantic memory. DISCUSSION: Loneliness may relate to AD through multiple pathways involving cerebrovascular pathology and cognitive reserve. HIGHLIGHTS: Loneliness was associated with worse cognition in five domains. Loneliness was associated with the presence of microinfarcts. Loneliness moderated cognition-neuropathology associations. Transportability methods can provide insight into selection bias.

DNA Methylation Age Acceleration Mediates the Relationship between Systemic Inflammation and Cognitive Impairment.

Background: Chronic inflammation and DNA methylation are potential mechanisms in dementia etiology. The linkage between inflammation and DNA methylation age acceleration in shaping dementia risk is understudied. We explored the association of inflammatory cytokines with cognitive impairment and whether DNA methylation age acceleration mediates this relationship. Methods: In a subset of the 2016 wave of the Health and Retirement Study (n=3,346, age>50), we employed logistic regression to estimate the associations between each inflammatory cytokine (interleukin-6 (IL-6), C-reactive protein (CRP), and insulin-like growth factor-1 (IGF-1)), and both Langa-Weir classified cognitive impairment non-dementia and dementia, respectively. We calculated DNA methylation age acceleration residuals by regressing GrimAge on chronologic age. We tested if DNA methylation age acceleration mediated the relationship between systemic inflammation and cognitive impairment, adjusting for sociodemographic, behavioral factors, chronic conditions, and cell type proportions. Results: The prevalence of cognitive impairment was 16%. In the fully-adjusted model, participants with a doubling of IL-6 levels had 1.12 (95% CI: 1.02-1.22) times higher odds of cognitive impairment. Similar associations were found for CRP and IGF-1. Participants with a doubling of IL-6 levels had 0.77 (95% CI: 0.64, 0.90) years of GrimAge acceleration. In mediation analyses with each cytokine as predictor separately, 17.7% (95% CI: 7.0%, 50.9%) of the effect of IL-6 on cognitive impairment was mediated through DNA methylation age acceleration. Comparable mediated estimates were found for CRP and IGF-1. Conclusions: Systemic inflammation is associated with cognitive impairment, with suggestive evidence that this relationship is partially mediated through DNA methylation age acceleration.

The association of sociodemographic factors with total and item-level semantic fluency metrics.

OBJECTIVE: We aimed to estimate the association of age, education, and sex/gender with semantic fluency performance as measured by the standard total number of words as well as novel item-level metrics and to descriptively compare associations across cohorts with different recruitment strategies and sample compositions. METHOD: Cross-sectional data from 2,391 individuals from three cohorts were used: Washington Heights/Inwood Columbia Aging Project, a community-based cohort; Second Manifestations of ARTerial disease-Magnetic Resonance, a clinic-based cohort; and African American Alzheimer's Disease Genetics Study, a volunteer-based cohort. Total number of correct words and six item-level semantic fluency metrics were included as main outcomes: average cluster size, number of cluster switches, lexical/Zipf frequency, age of acquisition, and lexical decision response time. General linear models were run separately in each cohort to model the association between sociodemographic variables and semantic fluency metrics. RESULTS: Across cohorts, older age was associated with a lower total score and fewer cluster switches. Higher level of education was associated with naming more words, performing more cluster switches, and naming words with a longer lexical decision response time, lower frequency of occurrence, or later age of acquisition. Being female compared to male was associated with naming fewer words, smaller cluster sizes, naming words with a longer lexical decision response time, and lower age of acquisition. The effects varied in strength but were in a similar direction across cohorts. CONCLUSIONS: Item-level semantic fluency metrics-similar to the standard total score-are sensitive to the effects of age, education, and sex/gender. The results suggest geographical, cultural, and cross-linguistic generalizability of these sociodemographic effects on semantic fluency performance. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Interactions among neighborhood conditions, sleep quality, and episodic memory across the adult lifespan.

OBJECTIVES: On average, adults racialized as non-Hispanic Black and Hispanic sleep more poorly than adults racialized as non-Hispanic White (hereafter, Black, Hispanic, White), but associations between factors that may moderate sleep-memory associations in these groups, such as neighborhood conditions, are unclear. Poorer neighborhood conditions (e.g. lower neighborhood cohesion) may be negatively associated with sleep quality and multiplicatively influence sleep-memory associations. We hypothesized lower ratings of neighborhood conditions would be associated with poorer sleep quality and moderate the association between sleep quality and episodic memory, especially in Black and Hispanic adults, who are disproportionately situated in poor neighborhood conditions. DESIGN: Seven-hundred-thirty-six adults across the adult lifespan (27-89 years) were recruited from the northern Manhattan community as a part of the Offspring Study of Racial and Ethnic Disparities in Alzheimer's disease. Sleep quality was assessed using a modified version of the Pittsburgh Sleep Quality Index, and episodic memory was evaluated with the Buschke Selective Reminding Test. With multiple regression models, we measured associations between perceived neighborhood conditions and sleep quality and the interaction between sleep quality and neighborhood conditions on episodic memory stratified by racial/ethnic and gender identity groups. RESULTS: Overall, poorer neighborhood conditions were associated with poorer sleep quality. In Black and Hispanic women, the sleep-memory association was moderated by neighborhood conditions. With more favorable neighborhood conditions, Black women showed an association between higher sleep quality and higher memory performance, and Hispanic women showed a protective effect of neighborhood (higher memory even when sleep quality was poor). CONCLUSION: Poorer neighborhood experiences may contribute to poorer sleep quality across groups. In Black and Hispanic women, the association between sleep quality and episodic memory performance was dependent upon neighborhood conditions. These findings may inform tailored, structural level sleep interventions, aimed to improve neighborhood experiences and thereby sleep quality and episodic memory.

Summer of Translational Aging Research for Undergraduates (STAR U): Short-term outcomes of a training program to advance diversity in aging research.

Purpose: The Summer of Translational Aging Research for Undergraduates (STAR U) program, funded by the National Institute on Aging and the Alzheimer's Association, aims to advance diversity in aging research through undergraduate education. Here, we evaluate the effectiveness of the program in cultivating a diverse cohort of scientists from underrepresented backgrounds. Method: Forty-eight (96%) of 50 STAR U alumni completed a program evaluation survey between April and August 2023. The survey collected data on demographic characteristics of the alumni, educational/career goals, program experiences, and post-program outcomes, including information about continued education and scientific engagement. Results: Ninety-one percent of respondents indicated that STAR U was "extremely significant" or "very significant" in influencing them to pursue a career in science, and 93% found STAR U to be effective in influencing decisions to pursue a career in aging research specifically. Forty one percent of all respondents were already accepted or enrolled in science-related advanced degree programs, with half enrolled in doctoral degree programs. Of the students who were not enrolled in graduate school, 89% of respondents indicated they had plans to enroll in advanced degrees in the future. Respondents actively disseminated their research, with 10% of STAR U scholars reporting leading or co-authoring papers intended for publication in a peer-reviewed journal (10%). In fact, review of PubMed shows that to date, 22 students (44%) have a combined total of 44 publications in peer reviewed journals. Qualitative feedback underscored the program's impact on career exploration, as well as the impact of mentorship and the supportive environment provided by STAR U. Conclusions: The STAR U program shows promise as an impactful model for advancing diversity in the scientific workforce focused on aging research by strengthening scholars' goals for pursuing graduate education, careers in science, and research in aging in particular. Its individualized approach supports students in addressing challenges and fosters a supportive environment. STAR U serves as a catalyst for underrepresented students in STEM, showcasing the significance of tailored initiatives in promoting diversity and inclusion in aging research.

Development and validation of the Michigan Chronic Disease Simulation Model (MICROSIM).

Strategies to prevent or delay Alzheimer's disease and related dementias (AD/ADRD) are urgently needed, and blood pressure (BP) management is a promising strategy. Yet the effects of different BP control strategies across the life course on AD/ADRD are unknown. Randomized trials may be infeasible due to prolonged follow-up and large sample sizes. Simulation analysis is a practical approach to estimating these effects using the best available existing data. However, existing simulation frameworks cannot estimate the effects of BP control on both dementia and cardiovascular disease. This manuscript describes the design principles, implementation details, and population-level validation of a novel population-health microsimulation framework, the MIchigan ChROnic Disease SIMulation (MICROSIM), for The Effect of Lower Blood Pressure over the Life Course on Late-life Cognition in Blacks, Hispanics, and Whites (BP-COG) study of the effect of BP levels over the life course on dementia and cardiovascular disease. MICROSIM is an agent-based Monte Carlo simulation designed using computer programming best practices. MICROSIM estimates annual vascular risk factor levels and transition probabilities in all-cause dementia, stroke, myocardial infarction, and mortality in a nationally representative sample of US adults 18+ using the National Health and Nutrition Examination Survey (NHANES). MICROSIM models changes in risk factors over time, cognition and dementia using changes from a pooled dataset of individual participant data from 6 US prospective cardiovascular cohort studies. Cardiovascular risks were estimated using a widely used risk model and BP treatment effects were derived from meta-analyses of randomized trials. MICROSIM is an extensible, open-source framework designed to estimate the population-level impact of different BP management strategies and reproduces US population-level estimates of BP and other vascular risk factors levels, their change over time, and incident all-cause dementia, stroke, myocardial infarction, and mortality.

Effect of Population-Level Blood Pressure Treatment Strategies on Cardiovascular and Cognitive Outcomes.

BACKGROUND: The large and increasing number of adults living with dementia is a pressing societal priority, which may be partially mitigated through improved population-level blood pressure (BP) control. We explored how tighter population-level BP control affects the incidence of atherosclerotic cardiovascular disease (ASCVD) events and dementia. METHODS: Using an open-source ASCVD and dementia simulation analysis platform, the Michigan Chronic Disease Simulation Model, we evaluated how optimal implementation of 2 BP treatments based on the Eighth Joint National Committee recommendations and SPRINT (Systolic Blood Pressure Intervention Trial) protocol would influence population-level ASCVD events, global cognitive performance, and all-cause dementia. We simulated 3 populations (usual care, Eighth Joint National Committee based, SPRINT based) using nationally representative data to annually update risk factors and assign ASCVD events, global cognitive performance scores, and dementia, applying different BP treatments in each population. We tabulated total ASCVD events, global cognitive performance, all-cause dementia, optimal brain health, and years lived in each state per population. RESULTS: Optimal implementation of SPRINT-based BP treatment strategy, compared with usual care, reduced ASCVD events in the United States by ≈77 000 per year and produced 0.4 more years of stroke- or myocardial infarction-free survival when averaged across all Americans. Population-level gains in years lived free of ASCVD events were greater for SPRINT-based than Eighth Joint National Committee-based treatment. Survival and years spent with optimal brain health improved with optimal SPRINT-based BP treatment implementation versus usual care: the average patient with hypertension lived 0.19 additional years and 0.3 additional years in optimal brain health. SPRINT-based BP treatment increased the number of years lived without dementia (by an average of 0.13 years/person with hypertension), but increased the total number of individuals with dementia, mainly through more adults surviving to advanced ages. CONCLUSIONS: Tighter BP control likely benefits most individuals but is unlikely to reduce dementia prevalence and might even increase the number of older adults living with dementia.

"Hang Ups, Let Downs, Bad Breaks, Setbacks": Impact of Structural Socioeconomic Racism and Resilience on Cognitive Change Over Time for Persons Racialized as Black.

Introduction: Older adults racialized as Black experience higher rates of dementia than those racialized as White. Structural racism produces socioeconomic challenges, described by artist Marvin Gaye as "hang ups, let downs, bad breaks, setbacks" that likely contribute to dementia disparities. Robust dementia literature suggests socioeconomic factors may also be key resiliencies. Methods: We linked state-level data reflecting the racialized landscape of economic opportunity across the 20th Century from the U.S. Census (1930-2010) with individual-level data on cognitive outcomes from the U.S. Health and Retirement Study participants racialized as Black. A purposive sample of participants born after the Brown v. Board ruling (born 1954-59) were selected who completed the modified Telephone Interview for Cognitive Status between 2010 and 2020 (N=1381). We tested associations of exposure to structural racism and resilience before birth, and during childhood, young-adulthood, and midlife with cognitive trajectories in mid-late life using mixed-effects regression models. Results: Older adults born in places with higher state-level structural socioeconomic racism experienced a more rapid cognitive decline in later life compared to those with lower levels of exposure. In addition, participants born in places with higher levels of state-level structural socioeconomic resilience experienced slower cognitive change over time than their counterparts. Discussion: These findings reveal the impact of racist U.S. policies enacted in the past that influence cognitive health over time and dementia risk later in life.

Physical Activity Moderates the Relationship between Cardiovascular Disease Risk Burden and Cognition in Older Adults.

INTRODUCTION: Older individuals with a higher cardiovascular disease (CVD) burden have a higher risk for accelerated cognitive decline and dementia. Physical activity (PA) is an inexpensive and accessible preventive measure to CVD, cognitive impairment, and dementia. The current study examined (1) whether PA moderates the relationship between CVD burden and cognition and (2) whether the moderating effect of PA differs by race/ethnicity groups and by APOE-ɛ4 status. METHODS: Our cross-sectional study included participants from the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multiethnic, community-based, longitudinal study on aging and dementia among individuals aged 65 years and older who reside in northern Manhattan. All participants underwent an interview and a neuropsychological assessment for global cognition, memory, language, visuospatial, and speed functioning. RESULTS: In 2,122 older individuals without dementia, having a higher CVD burden was associated with worse cognitive scores for global, language, speed, and visuospatial cognitive functions. PA mitigated the relationship between CVD burden and visuospatial function. Furthermore, PA mitigated the association of CVD burden with global cognition, language, and visuospatial functions in APOE-ɛ4 carriers but not in non-carriers. DISCUSSION/CONCLUSION: Our study suggests that PA may mitigate the negative association between CVD and cognition, especially in APOE-ɛ4 carriers. The moderating effect of PA did not differ by race/ethnicity.

Racial and ethnic differences in the association between depressive symptoms and cognitive outcomes in older adults: Findings from KHANDLE and STAR.

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.

General cognitive ability in high school, attained education, occupational complexity, and dementia risk.

INTRODUCTION: We address the extent to which adolescent cognition predicts dementia risk in later life, mediated by educational attainment and occupational complexity. METHODS: Using data from Project Talent Aging Study (PTAS), we fitted two structural equation models to test whether adolescent cognition predicts cognitive impairment (CI) and Ascertain Dementia 8 (AD8) status simultaneously (NCognitive Assessment = 2477) and AD8 alone (NQuestionnaire = 6491) 60 years later, mediated by education and occupational complexity. Co-twin control analysis examined 82 discordant pairs for CI/AD8. RESULTS: Education partially mediated the effect of adolescent cognition on CI in the cognitive assessment aample and AD8 in the questionnaire sample (Ps < 0.001). Within twin pairs, differences in adolescent cognition were small, but intrapair differences in education predicted CI status. DISCUSSION: Adolescent cognition predicted dementia risk 60 years later, partially mediated through education. Educational attainment, but not occupational complexity, contributes to CI risk beyond its role as a mediator of adolescent cognition, further supported by the co-twin analyses. HIGHLIGHTS: Project Talent Aging Study follows enrollees from high school for nearly 60 years. General cognitive ability in high school predicts later-life cognitive impairment. Low education is a risk partially due to its association with cognitive ability.

Risk of Alzheimer's disease is associated with longitudinal changes in plasma biomarkers in the multi-ethnic Washington Heights-Hamilton Heights-Inwood Columbia Aging Project (WHICAP) cohort.

BACKGROUND: Alzheimer's disease (AD) biomarkers can help differentiate cognitively unimpaired (CU) individuals from mild cognitive impairment (MCI) and dementia. The role of AD biomarkers in predicting cognitive impairment and AD needs examination. METHODS: In 628 CU individuals from a multi-ethnic cohort, amyloid beta (Aß)42, Aß40, phosphorylated tau-181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were measured in plasma. RESULTS: Higher baseline levels of p-tau181/Aß42 ratio were associated with an increased risk of incident dementia. A biomarker pattern (with elevated Aß42/Aß40 but low p-tau181/Aß42) was associated with decreased dementia risk. Compared to CU, participants who developed MCI or dementia had a rapid decrease in this protective biomarker pattern reflecting AD-specific pathological change. DISCUSSION: Elevated levels of AD biomarker p-tau181/Aß42, by itself or combined with a low Aß42/Aß40 level, predicts clinically diagnosed AD. Individuals with a rapid change in these biomarkers may need close monitoring for the potential downward trajectory of cognition. HIGHLIGHTS: We discuss a multi-ethnic, urban community study of elderly individuals. The study consisted of a longitudinal assessment over 6 years with repeated clinical assessments. The study used blood-based biomarkers as predictors of mild cognitive impairment and Alzheimer's disease.

Factor structure of the Harmonized Cognitive Assessment Protocol neuropsychological battery in the Health and Retirement Study.

OBJECTIVE: The Harmonized Cognitive Assessment Protocol (HCAP) describes an assessment battery and a family of population-representative studies measuring neuropsychological performance. We describe the factorial structure of the HCAP battery in the US Health and Retirement Study (HRS). METHOD: The HCAP battery was compiled from existing measures by a cross-disciplinary and international panel of researchers. The HCAP battery was used in the 2016 wave of the HRS. We used factor analysis methods to assess and refine a theoretically driven single and multiple domain factor structure for tests included in the HCAP battery among 3,347 participants with evaluable performance data. RESULTS: For the eight domains of cognitive functioning identified (orientation, memory [immediate, delayed, and recognition], set shifting, attention/speed, language/fluency, and visuospatial), all single factor models fit reasonably well, although four of these domains had either 2 or 3 indicators where fit must be perfect and is not informative. Multidimensional models suggested the eight-domain model was overly complex. A five-domain model (orientation, memory delayed and recognition, executive functioning, language/fluency, visuospatial) was identified as a reasonable model for summarizing performance in this sample (standardized root mean square residual = 0.05, root mean square error of approximation = 0.05, confirmatory fit index = 0.94). CONCLUSIONS: The HCAP battery conforms adequately to a multidimensional structure of neuropsychological performance. The derived measurement models can be used to operationalize notions of neurocognitive impairment, and as a starting point for prioritizing pre-statistical harmonization and evaluating configural invariance in cross-national research.

Association of brain arterial diameters with demographic and anatomical factors in a multi-national pooled analysis of cohort studies.

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.

Chromosome 10q24.32 Variants Associate With Brain Arterial Diameters in Diverse Populations: A Genome-Wide Association Study.

BACKGROUND: Brain arterial diameters (BADs) are novel imaging biomarkers of cerebrovascular disease, cognitive decline, and dementia. Traditional vascular risk factors have been associated with BADs, but whether there may be genetic determinants of BADs is unknown. METHODS AND RESULTS: The authors studied 4150 participants from 6 geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). Brain arterial diameters for 13 segments were measured and averaged to obtain a global measure of BADs as well as the posterior and anterior circulations. A genome-wide association study revealed 14 variants at one locus associated with global BAD at genome-wide significance (P<5×10-8) (top single-nucleotide polymorphism, rs7921574; ß=0.06 [P=1.54×10-8]). This locus mapped to an intron of CNNM2. A trans-ancestry genome-wide association study meta-analysis identified 2 more loci at NT5C2 (rs10748839; P=2.54×10-8) and AS3MT (rs10786721; P=4.97×10-8), associated with global BAD. In addition, 2 single-nucleotide polymorphisms colocalized with expression of CNNM2 (rs7897654; ß=0.12 [P=6.17×10-7]) and AL356608.1 (rs10786719; ß=-0.17 [P=6.60×10-6]) in brain tissue. For the posterior BAD, 2 variants at one locus mapped to an intron of TCF25 were identified (top single-nucleotide polymorphism, rs35994878; ß=0.11 [P=2.94×10-8]). For the anterior BAD, one locus at ADAP1 was identified in trans-ancestry genome-wide association analysis (rs34217249; P=3.11×10-8). CONCLUSIONS: The current study reveals 3 novel risk loci (CNNM2, NT5C2, and AS3MT) associated with BADs. These findings may help elucidate the mechanism by which BADs may influence cerebrovascular health.

Childhood Maltreatment and Dementia Risk Factors in Midlife: A Prospective Investigation.

BACKGROUND: Previous studies have linked childhood adversities to dementia risk, yet most studies are cross-sectional in design and utilize retrospective self-reports to assess childhood experiences. These design characteristics make it difficult to establish temporal order and draw firm conclusions. OBJECTIVES: Using a longitudinal design, we sought to determine whether childhood maltreatment predicts dementia risk factors in middle adulthood. METHODS: Data have been obtained from a prospective cohort design study of children with documented cases of childhood maltreatment (ages 0-11 years at case identification) and demographically matched controls who were followed up and interviewed in middle adulthood. Outcomes were assessed through a medical examination and interview, and 807 of the cases that included blood collection at mean age 41. Dementia risk were investigated using 11 potentially modifiable risk factors. RESULTS: Compared to controls, individuals with histories of childhood maltreatment had a higher risk of low educational attainment, low social contact, smoking, and clinical depression, and a higher total number of dementia risk factors. In general, childhood maltreatment predicted a higher risk of dementia for females, males, and Black and White participants. Black maltreated participants had a greater risk for traumatic brain injury compared to Black controls. Physical abuse, sexual abuse, and neglect, each predicted a higher number of dementia risk factors in mid-life. CONCLUSION: These findings provide evidence that childhood maltreatment increases the risk for dementia in mid-life and has a demonstrable impact lasting over 30 years. Reducing the prevalence of mid-life dementia risk factors could reduce the risk of later-life dementia.

Linking Air Pollution Exposure to Blood-Based Metabolic Features in a Community-Based Aging Cohort with and without Dementia.

BACKGROUND: Long-term exposure to air pollution has been associated with changes in levels of metabolites measured in the peripheral blood. However, most research has been conducted in ethnically homogenous, young or middle-aged populations. OBJECTIVE: To study the relationship between the plasma metabolome and long-term exposure to three air pollutants: particulate matter (PM) less than 2.5µm in aerodynamic diameter (PM2.5), PM less than 10µm in aerodynamic diameter (PM10), and nitrogen dioxide (NO2) in an ethnically diverse, older population. METHODS: Plasma metabolomic profiles of 107 participants of the Washington Heights and Inwood Community Aging Project in New York City, collected from 1995-2015, including non-Hispanic white, Caribbean Hispanic, and non-Hispanic Black older adults were used. We estimated the association between each metabolic feature and predicted annual mean exposure to the air pollutants using three approaches: 1) A metabolome wide association study framework; 2) Feature selection using elastic net regression; and 3) A multivariate approach using partial-least squares discriminant analysis. RESULTS: 79 features associated with exposure to PM2.5 but none associated with PM10 or NO2. PM2.5 exposure was associated with altered amino acid metabolism, energy production, and oxidative stress response, pathways also associated with Alzheimer's disease. Three metabolites were associated with PM2.5 exposure through all three approaches: cysteinylglycine disulfide, a diglyceride, and a dicarboxylic acid. The relationship between several features and PM2.5 exposure was modified by diet and metabolic diseases. CONCLUSIONS: These relationships uncover the mechanisms through which PM2.5 exposure can lead to altered metabolic outcomes in an older population.

History of obstructive sleep apnea associated with incident cognitive impairment in white but not black individuals in a US national cohort study.

BACKGROUND: We sought to determine if risk for obstructive sleep apnea (OSA), a history of OSA, and/or treatment of OSA has a different association with incident cognitive impairment or cognitive decline in Black individuals and White individuals. METHODS: To determine whether the risk for OSA, a history of OSA, and/or treatment of OSA has a different association with incident cognitive impairment or cognitive decline in Black individuals and White individuals; data from the REasons for Geographic and Racial Differences in Stroke (REGARDS) was used. Participants that completed the sleep questionnaire module, had baseline cognitive assessment, and at least one cognitive assessment during follow-up were included. Risk of OSA was determined based on Berlin Sleep Questionnaire. History of sleep apnea was determined based on structured interview questions. Optimally treated OSA was defined as treated sleep apnea as at least 4 h of continuous positive airway pressure use per night for ≥5 nights per week. RESULTS: In 19,017 participants stratified by race, White participants with history of OSA were 1.62 times more likely to have incident cognitive impairment compared to White participants without history of OSA after adjusting for demographic characteristics, history, and lifestyle factors (OR = 1.62, 95% CI = 1.05-2.50, p-value = 0.03). This relationship was not seen in Black participants (OR = 0.92, 95% CI = 0.60-1.43, p-value = 0.72). DISCUSSION: A previous diagnosis of OSA is associated with incident cognitive impairment in White Americans but not Black Americans. Further investigations are required to determine the mechanism for this difference.

Harmonisation of later-life cognitive function across national contexts: results from the Harmonized Cognitive Assessment Protocols.

BACKGROUND: The Harmonized Cognitive Assessment Protocol (HCAP) is an innovative instrument for cross-national comparisons of later-life cognitive function, yet its suitability across diverse populations is unknown. We aimed to harmonise general and domain-specific cognitive scores from HCAP studies across six countries, and evaluate reliability and criterion validity of the resulting harmonised scores. METHODS: We statistically harmonised general and domain-specific cognitive function scores across publicly available HCAP partner studies in China, England, India, Mexico, South Africa, and the USA conducted between October, 2015 and January, 2020. Participants missing all cognitive test items in a given HCAP were excluded. We used an item banking approach that leveraged common cognitive test items across studies and tests that were unique to studies. We generated harmonised factor scores to represent a person's relative functioning on the latent factors of general cognitive function, memory, executive function, orientation, and language using confirmatory factor analysis. We evaluated the marginal reliability, or precision, of the factor scores using test information plots. Criterion validity of factor scores was assessed by regressing the scores on age, gender, and educational attainment in a multivariable analysis adjusted for these characteristics. FINDINGS: We included 21 144 participants from the six HCAP studies of interest (11 480 women [54·3%] and 9664 [45·7%] men), with a median age of 69 years (IQR 64-76). Confirmatory factor analysis models of cognitive function in each country fit well: 31 (88·6%) of 35 models had adequate or good fit to the data (comparative fit index ≥0·90, root mean square error of approximation ≤0·08, and standardised root mean residual ≤0·08). Marginal reliability of the harmonised general cognitive function factor was high (>0·9) for 19 044 (90·1%) of 21 144 participant scores across the six countries. Marginal reliability of the harmonised factor was above 0·85 for 19 281 (91·2%) of 21 142 participant factor scores for memory, 7805 (41·0%) of 19 015 scores for executive function, 3446 (16·3%) of 21 103 scores for orientation, and 4329 (20·5%) of 21 113 scores for language. In each country, general cognitive function scores were lower with older age and higher with greater levels of educational attainment. INTERPRETATION: We statistically harmonised cognitive function measures across six large population-based studies of cognitive ageing. These harmonised cognitive function scores empirically reflect comparable domains of cognitive function among older adults across the six countries, have high reliability, and are useful for population-based research. This work provides a foundation for international networks of researchers to make improved inferences and direct comparisons of cross-national associations of risk factors for cognitive outcomes in pooled analyses. FUNDING: US National Institute on Aging.

Memory and language cognitive data harmonization across the United States and Mexico.

INTRODUCTION: We used cultural neuropsychology-informed procedures to derive and validate harmonized scores representing memory and language across population-based studies in the United States and Mexico. METHODS: Data were from the Health and Retirement Study Harmonized Cognitive Assessment Protocol (HRS-HCAP) and the Mexican Health and Aging Study (MHAS) Ancillary Study on Cognitive Aging (Mex-Cog). We statistically co-calibrated memory and language domains and performed differential item functioning (DIF) analysis using a cultural neuropsychological approach. We examined relationships among harmonized scores, age, and education. RESULTS: We included 3170 participants from the HRS-HCAP (Mage = 76.6 [standard deviation (SD): 7.5], 60% female) and 2042 participants from the Mex-Cog (Mage = 68.1 [SD: 9.0], 59% female). Five of seven memory items and one of twelve language items demonstrated DIF by study. Harmonized memory and language scores showed expected associations with age and education. DISCUSSION: A cultural neuropsychological approach to harmonization facilitates the generation of harmonized measures of memory and language function in cross-national studies. HIGHLIGHTS: We harmonized memory and language scores across studies in the United States and Mexico.A cultural neuropsychological approach to data harmonization was used.Harmonized scores showed minimal measurement differences between cohorts.Future work can use these harmonized scores for cross-national studies of Alzheimer's disease and related dementias.