# The epigenetics of dementia risk in the Million Veteran Program

> **NIH VA I01** · VA BOSTON HEALTH CARE SYSTEM · 2024 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 10918836
- **Project number:** 1I01BX006549-01
- **Recipient organization:** VA BOSTON HEALTH CARE SYSTEM
- **Principal Investigator:** MARK W MILLER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10918836

## Citation

> US National Institutes of Health, RePORTER application 10918836, The epigenetics of dementia risk in the Million Veteran Program (1I01BX006549-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10918836. Licensed CC0.

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