Deirdre M. O'SHea

1. Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disorder characterized by cognitive decline sufficient to interfere with daily activities or social/occupational function (i.e....

MethylCog is a 29-CpG blood DNA methylation (DNAm) score developed to index general cognitive ability (g). Whether it captures cognition-related information associated with later cognitive performance that is not fully represented by blood-based biomarkers of Alzheimer’s disease and related dementias (ADRD) remains unclear. Using the held-out Health and Retirement Study Harmonized Cognitive Assessment Protocol (HRS-HCAP) test set from the original MethylCog study (N = 605), we examined associations with baseline g after adjustment for age, sex, education, apolipoprotein E (APOE) ε4 carrier status, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), phosphorylated tau 181 (p-tau181), and amyloid-β 42/40 ratio (Aβ42/40). Prospective associations with six-year follow-up g were examined after adjustment for baseline g, age, sex, education, and APOE ε4 carrier status, with additional adjustment for the ADRD biomarker panel. MethylCog remained associated with baseline g in the fully adjusted cross-sectional model (standardized β = .178, 95% CI: .111-.244, p < .001; ΔAdjR² = .025). MethylCog was also associated with six-year follow-up g after adjustment for baseline g and all covariates and biomarkers (standardized β = .101, 95% CI: .033-.170, p = .004; N = 331; ΔAdjR² = .007). Findings were similar among participants without baseline cognitive impairment. These findings provide preliminary evidence that a cognition-trained DNAm signature captures variation in later cognitive performance not fully represented by baseline cognition or available ADRD blood biomarkers.

Urban heat islands (UHIs) are areas of elevated surface temperature caused by limited vegetation and dense development. Extreme heat disproportionately affects older adults and may increase risk for Alzheimer’s disease (AD) and related dementias (ADRD), but few studies have examined whether cumulative neighborhood-level heat exposure is associated with cognitive decline or ADRD biomarkers. This study will investigate whether recent UHI exposure is associated with cognitive function; determine whether cumulative UHI exposure is associated with cognitive decline, plasma ADRD biomarkers, and brain imaging biomarkers; and evaluate whether UHI exposure is associated with ADRD risk factors, including physical inactivity, social isolation, and inflammation, and whether tree canopy mitigates heat-ADRD associations. The study includes 500 adults aged ≥50 years from the Healthy Brain Initiative cohort in South Florida. Geocoded residential addresses will be linked to satellite-derived land surface temperature data to quantify recent exposure at the baseline cognitive visit and cumulative exposure during the month before, and 1 and 5 years before baseline. Participants complete annual clinical and neuropsychological assessments, brain MRI, and blood collection for ADRD biomarkers. A sub-sample of 200 participants will wear smartwatches during two 3-week periods to capture GPS-based heat exposure, physical activity, and daily cognitive testing. Analyses will be replicated using the nationally representative Health and Retirement Study. Primary outcomes include cognitive domain scores, brain imaging measures, and preclinical AD status determined from plasma biomarkers. This study will provide comprehensive data on cumulative UHI exposure and ADRD risk by integrating cognitive assessment, neuroimaging, and biomarkers. Findings will clarify whether neighborhood heat represents a modifiable ADRD risk factor and inform urban greening and brain health promotion strategies.

INTRODUCTION: MethylCog is a 29-CpG blood DNA methylation (DNAm) proxy for general cognitive ability (g). Its incremental association with blood biomarkers of Alzheimer’s disease and related dementias (ADRD) and prospective cognitive ability remains unclear. METHODS: In the held-out test set from the original MethylCog study, we tested whether MethylCog explained baseline g beyond four ADRD blood biomarkers, and whether it predicted six-year follow-up g beyond baseline g and biomarkers. RESULTS: MethylCog showed a stronger age-adjusted association with baseline g than individual biomarkers (r=.368 vs absolute r=.083–.162). MethylCog added 10.0% variance beyond all four biomarkers cross-sectionally (p<.001) and predicted six-year follow-up g in the biomarker-adjusted model (β=.108, p=.002). No individual ADRD biomarker independently predicted follow-up g. DISCUSSION: MethylCog may provide cognition-related DNAm information complementary to blood-based ADRD biomarkers.

INTRODUCTION: Whether Alzheimer’s disease (AD) blood biomarker-cognition associations differ across cognitive domains, analytic context, and biomarker modeling strategy in population-based cohorts is unclear. METHODS: In 1,170 older adults from the Health and Retirement Study Harmonized Cognitive Assessment Protocol, we examined cross-sectional (2016) and prospective (2016-2022) associations of blood p-tau181, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and amyloid-β42/40 with memory, executive function, language, visuospatial ability, and global cognition using individual biomarker, principal components analysis-derived composite, and multibiomarker panel models. RESULTS: Cross-sectionally, NfL and GFAP showed the broadest associations. Prospectively, p-tau181 was independently associated with memory and global cognition, whereas GFAP was associated with executive function, memory, and global cognition. P-tau181 also showed relative memory-versus-executive selectivity. The comparatively best-fitting modeling approach differed by cognitive domain and analytic context. DISCUSSION: AD blood biomarker-cognition associations in community-dwelling older adults are domain-differentiated and context-dependent, supporting domain-specific outcomes and flexible biomarker modeling strategies.

INTRODUCTION: Heterogeneity in cognitive ability increases with age and predicts mild cognitive impairment (MCI) and dementia, but scalable blood‐based biomarkers are lacking. We developed and validated MethylCog, a parsimonious DNA methylation (DNAm) marker of general cognitive ability (g). METHODS: MethylCog was developed using elastic net regression on principal components analysis (PCA) ‐derived g in a population‐based cohort ( n = 2,069; training/test split) externally validated ( n = 112). Criterion validity, MCI discrimination, and specificity relative to GrimAge and Alzheimer's disease (AD) biomarkers were assessed. RESULTS: MethylCog (29 CpGs) predicted g in the test set ( R ² = 0.17) and external cohort ( R ² = 0.13), explaining ∼11% of variance beyond age and sex. MethylCog improved MCI discrimination beyond demographics (ΔAUC = 0.03–0.07) and outperformed GrimAge but did not add value beyond cognitive screeners. Exploratory analyses showed no significant associations with AD plasma biomarkers or MRI measures. DISCUSSION: MethylCog provides initial evidence that parsimonious DNAm scores can index individual differences in cognitive ability, with potential utility where direct assessment is unavailable.

Background: Healthy lifestyles may reduce dementia risk by helping build cognitive reserve across the life course and promoting resilience and better cognitive outcomes in late-life. Whether self-reported lifestyle changes are informative for assessing brain health remains unclear. Objective: To determine whether self-reported lifestyle changes (determinants) are associated with cognition, resilience, and Alzheimer's disease and related dementias (ADRD) biomarkers (outcomes), and whether these associations vary by sociodemographic characteristics and cognitive impairment status. Methods: Data was obtained from 260 adults (age-range: 50–92). Self-reported change (increase/no change, decrease) in diet and physical, cognitive, and social activity from age 25 to present was evaluated in relation to cognition, resilience, and biomarkers within a cross-sectional design. ANCOVA models adjusted for age, sex, race, ethnicity, and education were used to examine associations between lifestyle change and outcomes. Effect modification by sex, race, ethnicity, and cognitive impairment status was also tested. Results: Self-reported increases in physical activity and diet were associated with better cognition and higher resilience, while increases in social activity with higher resilience and larger amygdala volume. Associations were stronger when increases occurred in multiple lifestyle domains. Associations differed by cognitive impairment status; no variation by sex and race was observed. Conclusions: Increases in lifestyle behaviors relative to age 25 were associated with better cognitive and brain health outcomes, especially when increases occurred across multiple domains. These findings align with longitudinal evidence linking lifestyle engagement to cognitive aging and suggest that cross-sectional self-report of change may provide a useful proxy for estimating long-term lifestyle patterns.

INTRODUCTION: Epigenetic assays may support non‐invasive dementia risk stratification; community views on willingness and implementation remain under‐characterized. METHODS: In a survey of 425 adults ≥50 years old, we assessed the willingness for a hypothetical epigenetic test, implementation preferences, reactions to a high‐risk result, behavior‐change intentions, and reasons for not testing using multivariable models. RESULTS: Overall, 82.1% showed a willingness. Health literacy (odds ratio [OR] = 2.61) and Alzheimer's disease (AD) concern (OR = 2.06) increased that willingness; doctor dependence decreased it (OR = 0.62). The top drivers were perceived to be accuracy and speed. The preferred modality was a combination of biomarker and cognitive over biomarker‐only. Intended changes prioritized alcohol reduction, then diet, exercise, cognitive activity. Risk worry and insurance concerns exceeded stigma; higher literacy related to lower stigma, and epigenetics familiarity and AD worry related to higher insurance concern. The reasons for not testing were data privacy/accuracy concerns, logistics/costs, and needles. DISCUSSION: Findings support emphasizing test accuracy, turnaround, and governance/legal information when implementing DNAm testing for dementia risk.

Background: Key sociodemographics (e.g., nativity) plausibly related to Alzheimer's disease and related dementia (ADRD) risk have been investigated less frequently in relation to cognitive function, brain imaging, and blood-based biomarkers. Objective: To examine associations between multiple sociodemographics and ADRD/vascular outcomes among middle- to older-age adults. Methods: We used cross-sectional data on 341 Healthy Brain Initiative participants. Outcomes included cognitive domain scores (e.g., episodic memory, language), magnetic resonance imaging (MRI) (e.g., hippocampal and white matter hyperintensity volume), and blood-based biomarkers (e.g., Aβ _42/40 , pTau-217, NfL, GFAP). Sociodemographics included age, sex, racial group, Hispanic ethnicity, primary language, nativity, socioeconomic position, area deprivation, and living alone. Multivariable linear regression examined associations between sociodemographics and brain health outcomes. Results: Mean age was 69 ± 9 and 71% were women. Older individuals, women, Black and Hispanic individuals, those of lower socioeconomic position, and those born outside the US performed worse across various cognitive domains, while those who primarily spoke Spanish (versus English) scored better on episodic memory. Older individuals, women, and Hispanic individuals had worse brain health, and those identifying as other racial group and born outside of the US had better brain health measured via MRI. Older and Hispanic individuals had worse brain health and Black individuals and women had better brain health as measured via blood-based biomarkers. Conclusions: This study contributes to the growing number of studies identifying differences in ADRD/vascular biomarkers by sociodemographics. Additional studies are needed to assess whether social and economic determinants of health are associated with longitudinal change in ADRD/vascular biomarkers.

INTRODUCTION: This study examines the role of lifestyle factors in cognitive reserve among older adults, focusing on the moderating effect of apolipoprotein E (APOE) ε4 status.METHODS: Data from 157 participants aged 45 and older from the Healthy Brain Initiative (HBI) were analyzed. Cognitive reserve was estimated using residual scores from Cognivue Clarity tests after accounting for brain atrophy and white matter hyperintensities (WMHs). Lifestyle factors included education, occupational attainment, physical activity, social engagement, diet, and mindfulness. Structural equation models were conducted to assess interactions.RESULTS: Significant interactions were found between APOE ε4 status and mindfulness and social engagement on cognitive reserve, indicating stronger associations for APOE ε4 carriers.DISCUSSION: APOE ε4 carriers may benefit more from certain lifestyle factors, potentially through stress reduction and anti‐inflammatory pathways. These findings support integrating APOE ε4 genetic screening into personalized prevention strategies to enhance interventions aimed at preserving cognitive function and delaying dementia onset in at‐risk populations.Highlights: Mindfulness and social engagement have increased cognitive reserve in APOE ε4 carriers. Study uses residual scores from Cognivue Clarity tests to estimate cognitive reserve. APOE ε4 carriers show stronger associations with certain lifestyle factors on cognitive reserve. Personalized interventions could enhance cognitive resilience in genetically at‐risk populations. Comprehensive assessment of multiple lifestyle factors highlights targeted intervention benefits.