Specification curve analysis to identify heterogeneity in risk factors for dementia: findings from the UK Biobank.

BACKGROUND: In 2020, the Lancet Commission identified 12 risk factors as priorities for prevention of dementia, and other studies identified APOE e4/e4 genotype and family history of Alzheimer's disease strongly associated with dementia outcomes; however, it is unclear how robust these relationships are across dementia subtypes and analytic scenarios. Specification curve analysis (SCA) is a new tool to probe how plausible analytical scenarios influence outcomes. METHODS: We evaluated the heterogeneity of odds ratios for 12 risk factors reported from the Lancet 2020 report and two additional strong associated non-modifiable factors (APOE e4/e4 genotype and family history of Alzheimer's disease) with dementia outcomes across 450,707 UK Biobank participants using SCA with 5357 specifications across dementia subtypes (outcomes) and analytic models (e.g., standard demographic covariates such as age or sex and/or 14 correlated risk factors). RESULTS: SCA revealed variable dementia risks by subtype and age, with associations for TBI and APOE e4/e4 robust to model specification; in contrast, diabetes showed fluctuating links with dementia subtypes. We found that unattributed dementia participants had similar risk factor profiles to participants with defined subtypes. CONCLUSIONS: We observed heterogeneity in the risk of dementia, and estimates of risk were influenced by the inclusion of a combination of other modifiable risk factors; non-modifiable demographic factors had a minimal role in analytic heterogeneity. Future studies should report multiple plausible analytic scenarios to test the robustness of their association. Considering these combinations of risk factors could be advantageous for the clinical development and evaluation of novel screening models for different types of dementia.

Rural versus Urban Residence in Adulthood and Incident Cognitive Impairment.

INTRODUCTION: Rural versus urban living is a social determinant of cognitive health. We estimated the association of rural versus urban residence in the USA with incident cognitive impairment (ICI) and assessed effect heterogeneity by sociodemographic, behavioral, and clinical factors. METHODS: The Reasons for Geographic and Racial Differences in Stroke Study (REGARDS) is a population-based prospective observational cohort of 30,239 adults, 57% female, 36% Black, aged 45+ years, sampled from 48 contiguous states in the USA in 2003-2007. We analyzed 20,878 participants who at baseline were cognitively intact with no history of stroke and had ICI assessed on average 9.4 years later. We classified participants' home addresses at baseline as urban (population ≥50,000), large rural (10,000-49,999), or small rural (≤9,999) by Rural-Urban Commuting Area codes. We defined ICI as ≥1.5 SD below the mean on at least 2 of the following tests: word list learning, word list delayed recall, and animal naming. RESULTS: Participants' home addresses were 79.8% urban, 11.7% large rural, and 8.5% small rural. ICI occurred in 1,658 participants (7.9%). Small rural residents had higher odds of ICI than urban residents, adjusted for age, sex, race, region, and education (OR = 1.34 [95% CI: 1.10, 1.64]), and after further adjustment for income, health behaviors, and clinical characteristics (OR = 1.24 [95% CI: 1.02, 1.53]). Former smoking versus never, nondrinking versus light alcohol drinking, no exercise versus ≥4 times/week, CES-D depressive symptom score of 2 versus 0, and fair versus excellent self-rated health had stronger associations with ICI in small rural areas than in urban areas. For example, in urban areas, lack of exercise was not associated with ICI (OR = 0.90 [95% CI: 0.77, 1.06]); however, lack of exercise combined with small rural residence was associated with 1.45 times the odds of ICI compared with ≥4 bouts of exercise/week in urban areas (95% CI: 1.03, 2.03). Overall, large rural residence was not associated with ICI; however, black race, hypertension, and depressive symptoms had somewhat weaker associations with ICI, and heavy alcohol drinking a stronger association with ICI, in large rural areas than in urban areas. CONCLUSION: Small rural residence was associated with ICI among USA adults. Further research to better understand why rural residents are at higher risk for developing ICI and mechanisms to ameliorate that risk will support efforts to advance rural public health.

Genetic Risk of Alzheimer's Disease and Sleep Duration in Non-Demented Elders.

Growing evidence has suggested an association between sleep duration and Alzheimer's disease (AD), but it is unclear if sleep duration is a manifestation of the AD disease process. We studied whether genetic liability for AD predicts sleep duration using a genetic risk score (GRS) for AD (AD-GRS), in 406,536 UK Biobank participants with European ancestry and without dementia at enrollment. Higher AD-GRS score was associated with shorter sleep (b = -0.014, 95% confidence interval [CI] = -0.022 to -0.006), especially in those aged 55+. Using AD-GRS as an instrumental variable for AD diagnosis, incipient AD reduced sleep duration by 1.87 hours (95% CI = 0.96, 2.78). Short sleep duration might be an early marker of AD. ANN NEUROL 2021;89:177-181.

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease.

Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10-9), MINK1 (chromosome 17, meta-p = 1.98 × 10-7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10-7 and closest gene = MYBPC3, meta-p = 5.62 × 10-8). In a large 'AD-by-proxy' cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.

Social Integration and Reduced Risk of Coronary Heart Disease in Women: The Role of Lifestyle Behaviors.

RATIONALE: Higher social integration is associated with lower cardiovascular mortality; however, whether it is associated with incident coronary heart disease (CHD), especially in women, and whether associations differ by case fatality are unclear. OBJECTIVES: This study sought to examine the associations between social integration and risk of incident CHD in a large female prospective cohort. METHODS AND RESULTS: Seventy-six thousand three hundred and sixty-two women in the Nurses' Health Study, free of CHD and stroke at baseline (1992), were followed until 2014. Social integration was assessed by a simplified Berkman-Syme Social Network Index every 4 years. End points included nonfatal myocardial infarction and fatal CHD. Two thousand three hundred and seventy-two incident CHD events occurred throughout follow-up. Adjusting for demographic, health/medical risk factors, and depressive symptoms, being socially integrated was significantly associated with lower CHD risk, particularly fatal CHD. The most socially integrated women had a hazard ratio of 0.55 (95% confidence interval, 0.41-0.73) of developing fatal CHD compared with those least socially integrated (P for trend <0.0001). When additionally adjusting for lifestyle behaviors, findings for fatal CHD were maintained but attenuated (P for trend =0.02), whereas the significant associations no longer remained for nonfatal myocardial infarction. The inverse associations between social integration and nonfatal myocardial infarction risk were largely explained by health-promoting behaviors, particularly through differences in cigarette smoking; however, the association with fatal CHD risk remained after accounting for these behaviors and, thus, may involve more direct biological mechanisms. CONCLUSIONS: Social integration is inversely associated with CHD incidence in women, but is largely explained by lifestyle/behavioral pathways.

Perceived Stress is Associated with Accelerated Monocyte/Macrophage Aging Trajectories in Clinically Normal Adults.

OBJECTIVES: Chronic stress is associated with poorer age-related cognition, but the mechanisms of this relationship are not well understood. Aging increases expression of activated macrophages, leading to exacerbated immune responses to stressors. We examined the impact of stress and aging on macrophage-related inflammation and cognition in clinically normal adults. METHODS: Three hundred eighty clinically normal adults were followed longitudinally (age M = 73 years; visit range: 1-8; M = 2.5 visits). Participants completed the Perceived Stress Scale, a neuropsychological battery, and blood draws. Plasma was analyzed for cytokines related to macrophage function (interleukin 6, tumor necrosis factor alpha, macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta). Linear mixed-effects examined the effects of age, baseline stress, and their interaction predicting macrophage cytokines, adjusting for sex, education, and depressive symptoms. Latent growth curve models assessed the mediating role of macrophage cytokines in the relationship between age and cognition in high or low stress. RESULTS: Baseline perceived stress interacted with age to predict macrophage cytokines longitudinally. Specifically, high-stress adults demonstrated accelerated age-related elevations in macrophage cytokines across time. Macrophage cytokines negatively tracked with executive functioning longitudinally. Macrophage cytokines mediated 19% of the relationship between age and executive function in high-stress, but not low-stress, adults. CONCLUSIONS: Our data provide evidence of accelerated immune aging among individuals with high stress. Elevated macrophage cytokine trajectories mediated the effect of age on executive function only in individuals with high stress, suggesting these constructs may be more tightly linked in elevated stress contexts. Stress interventions are warranted to optimize immune aging, with possible downstream cognitive benefits among even clinically normal adults.

The effect of the Infant Health and Development Program on special education use at school age.

OBJECTIVES: To evaluate the effect of an intensive early intervention on special service use at school-age. STUDY DESIGN: The Infant Health and Development Program was a randomized controlled trial of an intervention for low birth weight (<2500 g) infants ages 0-3 years. We used multivariate logistic regression to test the association between intervention and risk of special education, remedial reading and math, and speech therapy at age 8 years. We also compared rates of service use between study arms among those with learning disabilities (LDs). RESULTS: There were 875 complete cases at 8-year follow-up. There were no statistically significant differences between groups in risk of special education (risk ratio [RR] 0.86, 95% CI 0.64-1.15), remedial reading (RR 0.88, 95% CI 0.68-1.14), remedial math (RR 0.92, 95% CI 0.63-1.34), or speech therapy (RR 0.87, 95% CI 0.62-1.23). The treatment arms did not differ in rates of LDs, and service use for those with LDs was low and unaffected by study group. CONCLUSIONS: Early gains in IQ from infant interventions may not protect children as they face the educational demands of grade school. Only a fraction of those having a LD were receiving school-based support services, indicating a high level of unmet need among low birth weight children with disabilities.

Instrumental variable estimation in a survival context.

Bias due to unobserved confounding can seldom be ruled out with certainty when estimating the causal effect of a nonrandomized treatment. The instrumental variable (IV) design offers, under certain assumptions, the opportunity to tame confounding bias, without directly observing all confounders. The IV approach is very well developed in the context of linear regression and also for certain generalized linear models with a nonlinear link function. However, IV methods are not as well developed for regression analysis with a censored survival outcome. In this article, we develop the IV approach for regression analysis in a survival context, primarily under an additive hazards model, for which we describe 2 simple methods for estimating causal effects. The first method is a straightforward 2-stage regression approach analogous to 2-stage least squares commonly used for IV analysis in linear regression. In this approach, the fitted value from a first-stage regression of the exposure on the IV is entered in place of the exposure in the second-stage hazard model to recover a valid estimate of the treatment effect of interest. The second method is a so-called control function approach, which entails adding to the additive hazards outcome model, the residual from a first-stage regression of the exposure on the IV. Formal conditions are given justifying each strategy, and the methods are illustrated in a novel application to a Mendelian randomization study to evaluate the effect of diabetes on mortality using data from the Health and Retirement Study. We also establish that analogous strategies can also be used under a proportional hazards model specification, provided the outcome is rare over the entire follow-up.

Time Trends in Racial and Ethnic Disparities in Asthma Prevalence in the United States From the Behavioral Risk Factor Surveillance System (BRFSS) Study (1999-2011).

OBJECTIVES: We examined whether racial/ethnic disparities in the United States increased over time. METHODS: We analyzed data from 3 868 956 adults across the United States from the Behavioral Risk Factor Surveillance System from 1999 to 2011. We used random intercepts models (individuals nested in states) to examine racial/ethnic disparities and time trends in asthma lifetime and its current prevalence, adjusted for covariates. We also investigated the heterogeneity in asthma prevalence by ethnicity of the major zone of residence. RESULTS: Lifetime and current asthma prevalence were higher among non-Hispanic Black populations, with time trends highlighting increasing differences over time (b = 0.0078; 95% confidence interval [CI] = 0.0043, 0.0106). Lower odds ratios (ORs) of asthma were noted for Hispanic populations (OR = 0.74; 95% CI = 0.73, 0.76). Hispanics in states with more Puerto Rican residents reported greater risks of asthma (OR = 1.55; 95% CI = 1.24, 1.93) compared with Hispanics in states with larger numbers of Mexican or other ethnicities. CONCLUSIONS: Disparities in asthma prevalence by racial/ethnic groups increased in the last decade, with non-Hispanic Blacks and Puerto Rican Hispanics at greater risk. Interventions targeting asthma treatments need to recognize racial, ethnic, and geographic disparities.

Subjective cognitive concerns, episodic memory, and the APOE ε4 allele.

BACKGROUND: Subjective cognitive concerns may represent a simple method to assess likelihood of memory decline among apolipoprotein E (APOE) ε4 carriers. METHODS: We examined the relationship of self-reported subjective cognitive concerns, using seven specific cognitive concerns, with memory and memory decline over 6 years among APOE ε4 carriers and non-carriers from the Nurses' Health Study. RESULTS: In both groups, increasing subjective cognitive concern score predicted worse baseline memory and faster rates of subsequent memory decline, after adjustment for age, education and depression. The relation with baseline memory appeared statistically stronger in APOE ε4 carriers (P-interaction = 0.03). For memory decline, mean differences in slopes of episodic memory (95% CI) for 4 to 7 versus no concern = -0.05 (-0.10, 0.01) standard units in APOE ε4 carriers, and -0.04 (-0.08, -0.01) standard units in non-carriers. CONCLUSIONS: APOE ε4 carriers with self-assessed cognitive concerns appear to have worse memory, and possibly accelerated memory decline.

Leveraging electronic health records and knowledge networks for Alzheimer's disease prediction and sex-specific biological insights.

Identification of Alzheimer's disease (AD) onset risk can facilitate interventions before irreversible disease progression. We demonstrate that electronic health records from the University of California, San Francisco, followed by knowledge networks (for example, SPOKE) allow for (1) prediction of AD onset and (2) prioritization of biological hypotheses, and (3) contextualization of sex dimorphism. We trained random forest models and predicted AD onset on a cohort of 749 individuals with AD and 250,545 controls with a mean area under the receiver operating characteristic of 0.72 (7 years prior) to 0.81 (1 day prior). We further harnessed matched cohort models to identify conditions with predictive power before AD onset. Knowledge networks highlight shared genes between multiple top predictors and AD (for example, APOE, ACTB, IL6 and INS). Genetic colocalization analysis supports AD association with hyperlipidemia at the APOE locus, as well as a stronger female AD association with osteoporosis at a locus near MS4A6A. We therefore show how clinical data can be utilized for early AD prediction and identification of personalized biological hypotheses.

The association of neighborhood socioeconomic characteristics with cardiovascular health: A quasi-experimental study of refugees to Denmark.

Neighborhood socioeconomic disadvantage is associated with cardiovascular health, although it is unclear which specific aspects of neighborhoods matter most. We leveraged a natural experiment in which refugees to Denmark were quasi-randomly assigned to neighborhoods across the country during 1986-1998, creating variation in exposure to various aspects of neighborhood disadvantage. The cohort was followed through December 2018. Exposures included neighborhood-level family income, educational attainment, unemployment, and welfare transfers measured in the first neighborhood after arrival to Denmark. Outcomes included cardiovascular risk factors (hyperlipidemia, hypertension, diabetes and anxiety/depression) and cardiovascular disease (acute myocardial infarction and ischemic heart disease). Neighborhood-level income and education were most consistently associated with cardiovascular risk factors, whereas welfare transfers were most consistently associated with cardiovascular disease. Addressing these specific aspects of neighborhood disadvantage could therefore lower the risk of poor cardiovascular health among refugees. Future research is warranted to examine if results are generalizable to other immigrant groups, countries or time periods.

Influence of maternal age on birth and infant outcomes at 6 months: a cohort study with quantitative bias analysis.

BACKGROUND: Maternal age is increasingly recognized as a predictor of birth outcomes. Given the importance of birth and growth outcomes for children's development, wellbeing and survival, this study examined the effect of maternal age on infant birth and growth outcomes at 6 months and mortality. Additionally, we conducted quantitative bias analysis (QBA) to estimate the role of selection bias and unmeasured confounding on the effect of maternal age on infant mortality. METHODS: We used data from randomized-controlled trials (RCTs) of 21 555 neonates in Burkina Faso conducted in 2019-2020. Newborns of mothers aged 13-19 years (adolescents) and 20-40 years (adults) were enrolled in the study 8-27 days after birth and followed for 6 months. Measurements of child's anthropometric measures were collected at baseline and 6 months. We used multivariable linear regression to compare child anthropometric measures at birth and 6 months, and logistic regression models to obtain the odds ratio (OR) of all-cause mortality. Using multidimensional deterministic analysis, we assessed scenarios in which the difference in selection probability of adolescent and adult mothers with infant mortality at 6 months increased from 0% to 5%, 10%, 15% and 20% if babies born to adolescent mothers more often died during the first week or were of lower weight and hence were not eligible to be included in the original RCT. Using probabilistic bias analysis, we assessed the role of unmeasured confounding by socio-economic status (SES). RESULTS: Babies born to adolescent mothers on average had lower weight at birth, lower anthropometric measures at baseline, similar growth outcomes from enrolment to 6 months and higher odds of all-cause mortality by 6 months (adjusted OR = 2.17, 95% CI 1.35 to 3.47) compared with those born to adult mothers. In QBA, we found that differential selection of adolescent and adult mothers could bias the observed effect (OR = 2.24, 95% CI 1.41 to 3.57) towards the null [bias-corrected OR range: 2.37 (95% CI 1.49 to 3.77) to 2.84 (95% CI 1.79 to 4.52)], whereas unmeasured confounding by SES could bias the observed effect away from the null (bias-corrected OR: 2.06, 95% CI 1.31 to 2.64). CONCLUSIONS: Our findings suggest that delaying the first birth from adolescence to adulthood may improve birth outcomes and reduce mortality of neonates. Babies born to younger mothers, who are smaller at birth, may experience catch-up growth, reducing some of the anthropometric disparities by 6 months of age.

High school quality is associated with cognition 58 years later.

We leveraged a unique school-based longitudinal cohort-the Project Talent Aging Study-to examine whether attending higher quality schools is associated with cognitive performance among older adults in the United States (mean age = 74.8). Participants (n = 2,289) completed telephone neurocognitive testing. Six indicators of high school quality, reported by principals at the time of schooling, were predictors of respondents' cognitive function 58 years later. To account for school-clustering, multilevel linear and logistic models were applied. We found that attending schools with a higher number of teachers with graduate training was the clearest predictor of later-life cognition, and school quality mattered especially for language abilities. Importantly, Black respondents (n = 239; 10.5 percentage) were disproportionately exposed to low quality high schools. Therefore, increased investment in schools, especially those that serve Black children, could be a powerful strategy to improve later life cognitive health among older adults in the United States.

Does cognitive reserve shape cognitive decline?

OBJECTIVE: Cognitive reserve is associated with a lower risk of dementia, but the extent to which it shapes cognitive aging trajectories remains unclear. Our objective is to examine the impact of 3 markers of reserve from different points in the life course on cognitive function and decline in late adulthood. METHODS: Data are from 5,234 men and 2,220 women, mean age 56 years (standard deviation = 6) at baseline, from the Whitehall II cohort study. Memory, reasoning, vocabulary, and phonemic and semantic fluency were assessed 3× over 10 years. Linear mixed models were used to assess the association between markers of reserve (height, education, and occupation) and cognitive decline, using the 5 cognitive tests and a global cognitive score composed of these tests. RESULTS: All 3 reserve measures were associated with baseline cognitive function; the strongest associations were with occupation and the weakest with height. All cognitive functions except vocabulary declined over the 10-year follow-up period. On the global cognitive test, there was greater decline in the high occupation group (-0.27; 95% confidence interval [CI], -0.28 to -0.26) compared to the intermediate (-0.23; 95% CI, -0.25 to -0.22) and low groups (-0.21; 95% CI, -0.24 to -0.19); p = 0.001. The decline in reserve groups defined by education (p = 0.82) and height (p = 0.55) was similar. INTERPRETATION: Cognitive performance over the adult life course was remarkably higher in the high reserve groups. However, rate of cognitive decline did not differ between reserve groups with the exception of occupation, where there was some evidence of greater decline in the high occupation group.

Parental education as a predictor of offspring behavioural and physiological cardiovascular disease risk factors.

BACKGROUND: Childhood socio-economic disadvantage has been shown to be associated with an elevated rate of cardiovascular disease (CVD) events in adulthood. The objective of this study is to examine associations between mothers' and fathers' education and offspring CVD risk factors. METHODS: The Oslo Youth Study (n = 498) was initiated in 1979. Children (age 11-15 years) attending six schools and their parents were included. Information on education was collected for parents and participants. Participants were followed through 2006 (age 40 years). Information about physical activity, diet, smoking, binge drinking, body mass index (BMI), s-cholesterol, s-triglycerides and blood pressure was collected in 1981, 1991 and 2006. RESULTS: Fathers' education was inversely associated with participants' BMI at 15 and 25 years, cholesterol at 25 and 40 years, triglycerides at 25 years and systolic blood pressure at 15 and 25 years (regression coefficients -0.18 to -0.11; P < 0.05 for all). The effects were weakened after adjusting for participants' own education. Maternal education showed no association with these risk factors. After controlling for participants' own education, associations between parental education and behavioural risk factors in adulthood were few. CONCLUSION: Any impact of parental education on offspring CVD risk factors seemed to be mediated via subject's own education. Parental education offered little predictive capacity for offspring CVD risk factors.

Statins and Cognitive Decline in the Cardiovascular Health Study: A Comparison of Different Analytical Approaches.

BACKGROUND: Despite their well-established benefits for the prevention of cardiovascular disease, robust evidence on the effects of statins on cognition is largely inconclusive. We apply various study designs and analytical approaches to mimic randomized controlled trial effects from observational data. METHODS: We used observational data from 5 580 participants enrolled in the Cardiovascular Health Study from 1989/1990 to 1999/2000. We conceptualized the cohort as an overlapping sequence of nonrandomized trials. We compared multiple selection (eligible population, prevalent users, new users) and analytic approaches (multivariable adjustment, inverse-probability treatment weights, propensity score matching) to evaluate the association between statin use and 5-year change in global cognitive function, assessed using the Modified Mini-Mental State Examination (3MSE). RESULTS: When comparing prevalent users to nonusers (N = 2 772), statin use was associated with slower cognitive decline over 5 years (adjusted annual change in 3MSE = 0.34 points/year; 95% CI: 0.05-0.63). Compared to prevalent user design, estimates from new user designs (eg, comparing eligible statin initiators to noninitiators) were attenuated showing either null or negative association, though not significant. For example, in a propensity score-matched sample of statin-eligible individuals (N = 454), the annual 3MS change comparing statin initiators to noninitiators was -0.21 points/year (95% CI: -0.81 to 0.39). CONCLUSIONS: The association of statin use and cognitive decline is attenuated toward the null when using rigorous analytical approaches that more closely mimic randomized controlled trials. Point estimates, even within the same study, may vary depending on the analytical methods used. Further studies that leverage natural or quasi experiments around statin use are needed to replicate our findings.

Measuring Cognitive Health in Ethnically Diverse Older Adults.

OBJECTIVES: Understanding racial/ethnic disparities in late-life cognitive health is a public health imperative. We used baseline data from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study to examine how age, education, gender, and clinical diagnosis, a proxy for brain health, are associated with cross-sectional measures of cognition in diverse racial/ethnic groups. METHODS: Comprehensive measures of cognition were obtained using the Spanish and English Neuropsychological Assessment Scales and the National Institutes of Health Toolbox Cognitive Health Battery in a sample of 1,695 KHANDLE participants (Asians 24%, Blacks 26%, Latinos 20%, Whites 29%). A 25% random subsample was clinically evaluated and diagnosed with normal cognition, mild cognitive impairment (MCI), or dementia. Cognitive test scores were regressed on core demographic variables and diagnosis in the combined sample and in multiple group analyses stratified by racial/ethnic group. RESULTS: Race/ethnicity and education were variably associated with test scores with strongest associations with tests of vocabulary and semantic memory. Older age was associated with poorer performance on all measures, and gender differences varied across cognitive tests. Clinical diagnosis of MCI or dementia was associated with average decrements in test scores that ranged from -0.41 to -0.84 SD, with largest differences on tests of executive function and episodic memory. With few exceptions, associations of demographic variables and clinical diagnosis did not differ across racial/ethnic groups. DISCUSSION: The robust associations of cognitive test results with clinical diagnosis independent of core demographic variables and race/ethnicity support the validity of cognitive tests as indicators for brain health in diverse older adults.

Cross-national Differences in the Association Between Retirement and Memory Decline.

OBJECTIVE: Retirement is a potential trigger for cognitive aging as it may be a stressful life event accompanied by changes in everyday activities. However, the consequences of retirement may differ across institutional contexts which shape retirement options. Comparing memory trajectories before and after retirement in 17 European countries, this study aims to identify cross-national differences in the association between retirement and memory decline. METHOD: Respondents to the longitudinal Survey of Health, Aging, and Retirement in Europe (SHARE; N = 8,646) aged 50+ who were in paid work at baseline and retired during the observation period completed up to 6 memory assessments (immediate and delayed word recall) over 13 years. Three-level (time points, individuals, and countries) linear mixed models with country-level random slopes for retirement were estimated to evaluate whether memory decline accelerated after retirement and if this association differed between countries. RESULTS: On average, retirement was associated with a moderate decrement in word recall (b = -0.273, 95% CI -0.441, -0.104) and memory decline accelerated after retirement (b = -0.044, 95% CI -0.070, -0.018). Significant between-country heterogeneity in memory decline after retirement existed (variance = 0.047, 95% CI (0.013, 0.168). Memory decline after retirement was more rapid in Italy, Greece, Czech Republic, Poland, Portugal, and Estonia compared to Northern and Central European countries. DISCUSSION: Memory decline postretirement was faster in Mediterranean and eastern European countries, which are characterized by less generous welfare systems with comparatively low pension benefits. Evaluation of resources that could protect retirees from memory decline would be valuable.

Excess mortality associated with the COVID-19 pandemic among Californians 18-65 years of age, by occupational sector and occupation: March through November 2020.

BACKGROUND: Though SARS-CoV-2 outbreaks have been documented in occupational settings and in-person essential work has been suspected as a risk factor for COVID-19, occupational differences in excess mortality have, to date, not been examined. Such information could point to opportunities for intervention, such as vaccine prioritization or regulations to enforce safer work environments. METHODS AND FINDINGS: Using autoregressive integrated moving average models and California Department of Public Health data representing 356,188 decedents 18-65 years of age who died between January 1, 2016 and November 30, 2020, we estimated pandemic-related excess mortality by occupational sector and occupation, with additional stratification of the sector analysis by race/ethnicity. During these first 9 months of the COVID-19 pandemic, working-age adults experienced 11,628 more deaths than expected, corresponding to 22% relative excess and 46 excess deaths per 100,000 living individuals. Sectors with the highest relative and per-capita excess mortality were food/agriculture (39% relative excess; 75 excess deaths per 100,000), transportation/logistics (31%; 91 per 100,000), manufacturing (24%; 61 per 100,000), and facilities (23%; 83 per 100,000). Across racial and ethnic groups, Latino working-age Californians experienced the highest relative excess mortality (37%) with the highest excess mortality among Latino workers in food and agriculture (59%; 97 per 100,000). Black working-age Californians had the highest per-capita excess mortality (110 per 100,000), with relative excess mortality highest among transportation/logistics workers (36%). Asian working-age Californians had lower excess mortality overall, but notable relative excess mortality among health/emergency workers (37%), while White Californians had high per-capita excess deaths among facilities workers (70 per 100,000). CONCLUSIONS: Certain occupational sectors are associated with high excess mortality during the pandemic, particularly among racial and ethnic groups also disproportionately affected by COVID-19. In-person essential work is a likely venue of transmission of coronavirus infection and must be addressed through vaccination and strict enforcement of health orders in workplace settings.