Dan Mungas’s research while affiliated with University of California, Davis and other places

Positive childhood experiences (PCEs) have unknown effects on late life cognition and Alzheimer’s Disease biomarkers. We examined 406 Asian, 1179 Black, 349 Latinx, and 498 White KHANDLE and STAR study participants with data on PCEs, longitudinal cognitive measures, MRI (n = 560), and amyloid PET (n = 281). We conducted mediation and multigroup models within the structural equation modeling framework allowing us to examine the direct association of PCEs with episodic memory level and change as well as the indirect effects of PCEs through education. We additionally conducted linear regressions examining the association of PCEs with MRI and amyloid PET outcomes. Average participant age was 74 (53–90) and 62% were female. Overall, PCEs were positively associated with memory intercept and change. Education significantly mediated the association between PCEs and memory intercept. PCEs were not associated with hippocampal volume or amyloid burden in the combined sample or across individual ethnocultural groups. PCEs are positively related to episodic memory through the promotion of educational attainment.

Our nation is becoming increasingly diverse; however, few autopsy studies examine multiple ethnoracial groups, especially Hispanics. We examined differences in neuropathological diagnoses of 423 deceased participants with dementia from three ethnoracial groups (35 Black, 28 Hispanic, and 360 non-Hispanic White) evaluated at the University of California Davis Alzheimer’s Disease Center. We used novel applications of bootstrap resampling and logistic regression standardization to project neuropathological diagnostic rates for non-Hispanic Whites to minority sample characteristics to improve inference of findings. Alzheimer’s disease (AD) without significant cerebrovascular disease (CVD) or other dementia-related pathologies (AD (non-mixed)) was present in 15 Black (43%), 4 Hispanic (14%), and 156 (43%) non-Hispanic Whites. CVD sufficient to contribute to dementia was confirmed in 14 Black (40%), 15 Hispanic (54%), and 101 (28%) non-Hispanic White decedents. The observed CVD prevalence of 40% in Blacks exceeded the predicted 29% [95% CI: 22%-36%]. Despite being outside the 95% confidence interval, the difference between observed and predicted was not statistically significant after bootstrap testing. Conversely, for Hispanics, the observed proportion at 54% exceeded significantly the predicted prevalence of 24% from non-Hispanic Whites [95% CI: 16%-34%], avg. p = 0.008). An identical analysis using AD (non-mixed) as the outcome predicted AD (non-mixed) in Blacks averaging 41% [95% CI: 34%-48%], nearly equal to observed prevalence. For Hispanics, however, the observed proportion at 14%, was well below predictions (mean = 42%, 95% CI: 32%-53%], avg. p = 0.008). We conclude mixed diagnoses and CVD are more common in Hispanic and Black decedents than Non-Hispanic Whites with dementia in our cohort. The increased prevalence of vascular co-morbidity may be a potential opportunity to intervene more effectively in dementia treatment of those individuals.

Effect heterogeneity across individuals may help explain inconsistent evidence regarding effects of childhood adversity on brain health. We used harmonized Kaiser Healthy Aging and Diverse Life Experiences and Study of Healthy Aging in African Americans (n=617) data to evaluate heterogeneity in effect estimates of childhood adversity (z-score of 7 adverse childhood events factor score, dichotomized at median) on brain white matter hyperintensity volume (WMH, log transformed). We used an honest causal forest with augmented inverse probability weighting and 10-fold cross-validation to estimate conditional average treatment effects (CATEs); this approach captures complex heterogeneity better than traditional regression models. Candidate sources of heterogeneity included age at MRI, demographics, US southern birth, childhood SES measures and interactions between variables. Overall, exposure to at least median childhood adversity was associated with 0.14 higher log units of WMH (95% CI -0.06, 0.35) after covariate adjustment. The best linear fit model for the observed treatment effect had an out-of-bag predicted treatment effect coefficient of 0.81 (P-value=0.02), indicating the heterogeneity in the association. Individuals with estimated CATEs below the median estimated CATE were older (mean age 76.4y vs. 72.5y), more likely to be male (56% vs 63%), and more likely to report low childhood SES (55% vs. 74% average/well-off, 16% vs 7% ever went hungry). This is preliminary work in a relatively small sample; more work is needed to understand the impact of childhood adversity on late-life brain health, including differences across individual characteristics.

INTRODUCTION Childhood adversity harms neurodevelopment. Literature on late‐life brain health is limited, and findings on late‐life cognition are mixed. METHODS Pooling data from Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) and Study of Healthy Aging in African Americans (STAR) cohorts, we assessed the impact of childhood adversity (factor score from seven self‐reported items) on (a) executive function and verbal memory decline using linear mixed effects models (n = 2447), (b) structural magnetic resonance imaging (MRI) using linear regression (n = 618), and (c) amyloid positron emission tomography (PET) using generalized linear models (n = 331), all adjusting for early‐life demographic and socioeconomic confounders. RESULTS Childhood adversity was not associated with cognition except for a slightly faster decline in verbal memory (β̂$\hat \beta$ = −0.013 SD/year, 95% confidence interval [−0.025, −0.001]). Among neuroimaging outcomes, childhood adversity was associated with only larger temporal lobe volumes (β̂$\hat \beta$ = 0.092 SD [0.012, 0.173]). DISCUSSION More research evaluating sources of resilience, heterogeneity, and bias is needed to explain inconsistent findings across studies. Highlights We developed measurement models to capture childhood adversity in a diverse cohort. Childhood adversity was associated with a slightly faster verbal memory decline. We examined childhood adversity's effect on structural MRI and amyloid PET measures. Higher childhood adversity was associated with larger temporal lobe volumes.

INTRODUCTION Characterizing pathological changes in the brain that underlie cognitive impairment, including Alzheimer's disease and related disorders, is central to clinical concerns of prevention, diagnosis, and treatment. METHODS We describe the properties of a brain gray matter region (“Union Signature”) that is derived from four behavior‐specific, data‐driven signatures in a discovery cohort. RESULTS In a separate validation set, the Union Signature demonstrates clinically relevant properties. Its associations with episodic memory, executive function, and Clinical Dementia Rating Sum of Boxes are stronger than those of several standardly accepted brain measures (e.g., hippocampal volume, cortical gray matter) and other previously developed brain signatures. The ability of the Union Signature to classify clinical syndromes among normal, mild cognitive impairment, and dementia exceeds that of the other measures. DISCUSSION The Union Signature is a powerful, multipurpose correlate of clinically relevant outcomes and a strong classifier of clinical syndromes. Highlights Data‐driven brain signatures are potentially valuable in models of cognitive aging. In previous work, we outlined rigorous validation of signatures for memory. This work demonstrates a signature predicting multiple clinical measures. This could be useful in models of interventions for brain support of cognition.

Elucidating the mechanisms by which late-life neurodegeneration causes cognitive decline requires understanding why some individuals are more resilient than others to the effects of brain change on cognition (cognitive reserve). Currently, there is no way of measuring cognitive reserve that is valid (e.g., capable of moderating brain-cognition associations), widely accessible (e.g., does not require neuroimaging and large sample sizes), and able to provide insight into resilience-promoting mechanisms. To address these limitations, this study sought to determine whether a machine learning approach to combining standard clinical variables could (1) predict a residual-based cognitive reserve criterion standard and (2) prospectively moderate brain-cognition associations. In a training sample combining data from the University of California Davis and the Alzheimer’s Disease Neuroimaging Initiative-2 (ADNI-2) cohort (N=1665), we operationalized cognitive reserve using an MRI-based residual approach. An eXtreme Gradient Boosting machine learning algorithm was trained to predict this residual reserve index using three models: Minimal (basic clinical data, such as age, education, anthropometrics, and blood pressure), Extended (Minimal model plus cognitive screening, word reading, and depression measures), and Full (Extended model plus Clinical Dementia Rating and Everyday Cognition scale). External validation was performed in an independent sample of ADNI 1/3/GO participants (N=1640), which examined whether the effects of brain change on cognitive change were moderated by the machine learning models’ cognitive reserve estimates. The three machine learning models differed in their accuracy and validity. The Minimal model did not correlate strongly with the criterion standard (r=.23) and did not moderate the effects of brain change on cognitive change. In contrast, the Extended and Full models were modestly correlated with the criterion standard (r=.49 and .54, respectively) and prospectively moderated longitudinal brain-cognition associations, outperforming other cognitive reserve proxies (education, word reading). The primary difference between the Minimal model – which did not perform well as a measure of cognitive reserve – and the Extended and Full models – which demonstrated good accuracy and validity – is the lack of cognitive performance and informant-report data in the Minimal model. This suggests that basic clinical variables like anthropometrics, vital signs, and demographics are not sufficient for estimating cognitive reserve. Rather, the most accurate and valid estimates of cognitive reserve were obtained when cognitive performance data – ideally augmented by informant-reported functioning – was used. These results indicate that a dynamic and accessible proxy for cognitive reserve can be generated for individuals without neuroimaging data and gives some insight into factors that may promote resilience.

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.

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 (β^ 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 (β^ 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 (β^ sleep*time = −0.05, 95% CI, −0.07, −0.03) and verbal episodic memory β^ 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.

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 (β = 0.013, SE = 0.005, p = .004) and Openness (β = 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.

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 (β=0.117; 95% CI 0.052 to 0.182), three ACEs (β=0.075; 95% CI 0.007 to 0.143) and four or more ACEs (β=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.