The epigenetics of dementia risk in the Million Veteran Program

Alzheimer’s disease and related dementias (ADRD) affect approximately 10% of the US population, with prevalence increasing with age (e.g., 3% between ages 65–74 to 32% for people over the age of 85). The US Department of Veterans Affairs has placed a high priority on clinical research on ADRD, in part, because over

half of the veterans it serves are now over 65-years of age. In the past decade, considerable progress has been made in the identification of cerebrospinal fluid and positron emission tomography biomarkers of Alzheimer’s Disease and related dementias (ADRD) that are now used to aid in clinical diagnosis. However,

the high cost and invasiveness of these procedures has motivated the search for inexpensive, minimally invasive, and objective blood-based biomarkers of ADRD that can be used for diagnosis, prognostic evaluation, tracking treatment response, and monitoring disease progression. Using blood-based DNA methylation data from VA’s Million Veteran Program (MPV), this study will examine the epigenetic contributions

to ADRD risk with the aim of identifying DNA methylation loci that may eventually be used to guide the development of blood-based methylation assays for use with patients at risk for, or diagnosed with, ADRD. To do so, we will examine cross-sectional differences between ADRD cases and controls in blood-based DNA

methylation and use retrospective survival analyses to find DNA methylation markers that predict time to ADRD diagnosis during the 10+ year MVP observation window. We will evaluate the DNA methylation correlates of known AD genetic risk factors to identify epigenetic mechanisms that mediate the association

between genetic risk for ADRD and the manifestation of these conditions. We also propose to extend our previous research on the risk that posttraumatic stress disorder (PTSD) confers for ADRD by examining the influence of PTSD-associated DNA methylation changes on the development of ADRD. Finally, ADRD is

approximately twice as prevalent in Black Americans of African Ancestry compared to of White non-Hispanic individuals of European ancestry and the reasons for this disparity remain poorly understood. Compounding this problem is the fact that individuals of African Ancestry have been vastly underrepresented in genetic and

epigenetic studies of ADRD conducted to date. The cohort of MVP participants with genomewide genotypes and DNA methylation data is substantially enriched for representation of Black veterans (22%) . This offers an unprecedented opportunity to examine racial/ancestral epigenetic differences and advance understanding of

the biology underlying racial disparities in risk for ADRD.