DNA Methylation, Genetics, and Modifiable Risk Factors of Dementia in a Nationally Representative, Multi-Ethnic Cohort

Our goal is to determine the joint epigenetic and environmental contributions to ADRD risk that underlie these health disparities. Using existing epigenetic and genetic data, well-characterized dementia phenotypes, and diverse risk factor data, we will analyze a population representative, multi-ethnic aging sample from the Health and Retirement Study (HRS). We aim to (1) test the associations between DNA methylation and dementia phenotypes (prevalent, 8-year incident), stratified by race/ethnicity and test for effect modification by ADRD disparity-related factors (educational attainment, sex, urban/rural); (2) identify associations between longitudinal measures of modifiable risk factors for ADRD and DNA methylation, stratified by race/ethnicity and test for effect modification or mediation by ADRD disparity-related factors; and finally, (3) identify genetic polymorphisms controlling DNA methylation and whether these are enriched in dementia outcomes to evaluate the role of DNA methylation in disease development. This study will likely impact the field of Alzheimer’s research and contribute to public health because it will a) establish the relevance of DNA methylation on ADRD in multiple race/ethnicities; b) elucidate important biological epigenetic mechanisms; c) determine the combined and individual epigenetic-environment interplay contributions to ADRD; and d) consider the effects of sex, educational attainment, race/ethnicity, younger age groups, and urban/rural status in the same study where comparisons of relative contribution to risk can be made. Here, we have the opportunity to simultaneously and substantially improve our understanding of the genetic and environmental etiologic contributions to health disparities in ADRD. We are extending this work to include delirium with and without cognitive impairment.

The overall purpose of this proposal is to identify modifiable risk factors for Alzheimer’s disease and related dementias (including delirium) that influence DNA methylation and dementia status among groups at increased risk for dementia including women, minorities, rural inhabitants, and those with low educational attainment. Results from this proposal may provide an opportunity to identify epigenetic components that contribute to the prevalence and risk of dementia that could lead to a mechanistic understanding or targeted interventions that may substantially decrease the burden of Alzheimer’s disease and related dementias in the US population