Epigenetic mechanisms linking psychological stress with dementia risk in minoritized individuals

2024 Award: $147,167

Dementia has an enormous impact worldwide and disproportionately affects minoritized populations. Such health disparities have been attributed to discrimination and other social determinants of health, but the underlying mechanisms are unknown. This project examines the epigenetic mechanisms through which stress contributes to dementia risk in Black individuals.

Need/Problem: Alzheimer’s disease and related dementias (ADRD) have an enormous impact on individuals and societies, with Alzheimer’s disease alone currently afflicting ~6.7 million persons age 65 and older in the US. Importantly, ADRD disproportionately affect minoritized populations, with older Black adults having an estimated two to three times higher risk for cognitive impairment and dementia as compared to older non-Hispanic White adults. However, the mechanisms underlying this health disparity are unknown and no reliable biomarkers exist to guide early dementia interventions.

Grant Summary: While the mechanisms linking stress and dementia are unclear, epigenetics – the chemical changes that regulate genomic function without altering the genetic code – has emerged as a key link between environment and health. Stress can induce epigenetic changes at specific genomic sites that promote inflammation, and such effects can be particularly pronounced in Black adults. Moreover, Black individuals have been reported to exhibit heightened inflammation, likely as a biological consequence of chronic stress due to discrimination and other social determinants of health, and such inflammatory states are thought to be a key contributor to dementia. However, most studies to date have focused on individuals of European ancestry and epigenetic studies in minoritized populations are urgently needed. Our central hypothesis is that increased stress exposure drives epigenetic changes at inflammation-related genes and pathways that contribute to higher dementia risk in Black individuals.

Goals and Projected Outcomes: This interdisciplinary project is expected to advance understanding of how stress-driven epigenetic signatures dysregulate immune function and contribute to dementia risk in minoritized individuals.

Anthony Zannas, PhD

Grant Details: We will leverage the Jackson Heart Study (JHS), an aging cohort of Black individuals from the Jackson, Mississippi metropolitan area. Epigenomic data will be generated in a subset of JHS participants using available DNA and will be integrated with rich longitudinal data that include measures of stress burden, dementia outcomes, and relevant neuroimaging measures. Key identified epigenetic signatures of stress exposure and dementia risk will be experimentally dissected in immune cells derived from diverse donors. This line of research is expected to yield novel insights into the mechanisms linking psychosocial stress and dementia risk in minoritized individuals and to identify actionable molecular targets that can be leveraged to promote personalized interventions in high-risk populations.