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

PROJECT SUMMARY
Alzheimer’s disease and its related dementias (ADRD) represent the leading terminal forms of
dementia affecting a growing number of aging adults in the United States. Biomarkers of ADRD
risk, particularly among susceptible populations (ADRD risk is disproportionately high among
minorities, women, rural inhabitants, and people with lower education), represent a critical
knowledge gap. Thus, studies with sufficient sample sizes, concurrently assessing multiple
characteristics, such as educational attainment, environment, social, behavioral, lifestyle,
geographic, biology, and epigenetics, will be uniquely positioned to effectively test factors or
combinations of factors that create and sustain ADRD disparities. 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.

Grant Number: 5R01AG067592-05
NIH Institute/Center: NIH
Principal Investigator: Kelly Bakulski