ALZHEIMERS RESEARCH PROJECT: Epigenetics of Brain Aging/Health

National Institute On Aging

Investigators

Abstract

This project investigates how early life adversity, social determinants of health, and cardiovascular risk contribute to brain aging and cognitive decline, with a focus on epigenetic and imaging biomarkers. Using secondary datasets obtained through formal agreements with Columbia University (WHICAP and Offspring) and the CARDIA study, the research addresses fundamental questions about the biological embedding of stress and adversity across the life course and their impact on Alzheimer’s disease and related dementias (AD/ADRD). Study populations include: WHICAP and Offspring (~6,000 older adults, ages 65–90+, racially and ethnically diverse Black, White, and Latinx participants) and CARDIA (~5,000 adults followed from young adulthood into midlife, now ages 50–65, with repeated MRI assessments). Together, these cohorts provide complementary perspectives on life course risk and resilience. Scientific scope: In Offspring, analyses focus on DNA methylation measures of biological aging to test associations with socioeconomic status, vascular risk, and cognitive outcomes. In CARDIA, analyses evaluate the role of adverse childhood experiences (ACEs) in shaping brain aging trajectories, including white matter integrity, Alzheimer’s-like atrophy patterns, brain age acceleration indices, resting-state connectivity, and cerebral blood flow across multiple MRI modalities. WHICAP provides additional context for late-life cognitive and neuroimaging outcomes in racially and ethnically diverse older adults, supporting cross-cohort harmonization and validation. FY2025 progress: During this reporting period, data use agreements (DUAs) with Columbia University were finalized and de-identified datasets securely transferred to NIA. DNA methylation analyses in the Offspring study were initiated to examine biological aging signatures. In CARDIA, analyses are underway to assess the impact of ACEs on brain aging trajectories across structural, functional, and vascular MRI outcomes. Variable harmonization across cohorts has begun, and manuscripts based on Offspring DNAm and CARDIA analyses are in development. By harmonizing data across multiple cohorts and focusing on reproducible neuroimaging and epigenetic biomarkers, this project seeks to clarify mechanistic pathways of vulnerability and resilience in brain aging. The findings are expected to inform early prevention strategies, refine targets for intervention, and advance NIH priorities in addressing AD/ADRD, cardiovascular disease, and health disparities.