# The Role of Menopause-Driven DNA Damage and Epigenetic Dysregulation in Alzheimer s Disease

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $458,061

## Abstract

The Role of Menopause-Driven DNA Damage and Epigenetic Dysregulation in Alzheimer's Disease
PROJECT SUMMARY
Alzheimer's disease (AD) is the most common form of dementia worldwide, and 2 out of 3 patients are women.
A central explanation for this higher prevalence is thought to be the fluctuations in sex hormones as women
traverse menopause, prior to depletion of estrogen and progesterone in the post-menopause period. Menopause
has been reported to cause changes in epigenetic modifications, including histone acetylation which we and
others have shown to be important to prevent memory decline in AD models. We have also observed sex-specific
differences in AD-related genes in the brain of aged 3xTg-AD mice. Surprisingly little is known about the effects
of the menopausal transition on epigenetic mechanisms in the brain. Important, aging is strongly associated with
dysregulation of DNA damage repair, a process that has also been linked to menopause. Our preliminary data
analyzing some 300 human brains show that DNA Single Strand Break (SSB) repair enzymes are dysregulated
with age. We hypothesize that beyond its effects on reproductive stages in females, the menopause transition
modulates DNA damage response (DDR) and epigenetic mechanisms. This results in the biological differences
observed between female and male AD patients' mind and body. Existing AD models studying menopause use
ovariectomized mice, resulting in an abrupt termination of circulating estrogen. We believe this is not
representative of the menopause transition in women, in which peri-menopausal hormonal fluctuations can last
years. We have successfully implemented accelerated ovarian failure (AOF) in mice to mimic human
menopause. Here, using both the 3xTg-AD and 5xFAD mice under AOF, we will assess the effects of peri- and
post-menopause-like stages on DNA SSB, the epigenetic landscape and the subsequent impact on the
transcriptome and metabolic homeostasis in brain and blood in the context of AD. We developed a method to
map Single-Strand DNA breaks at Nucleotide Genome Level resolution (SSiNGLe) that allows high-resolution
analysis of DNA SSBs to determine the “Breakome age” of individuals, a potential novel biomarker of aging. We
will build network models (associating SSBs with transcriptome alterations) to better understand how
menopause-driven defects in DNA repair impact on known AD and Aging pathways. We will verify pathway
observations using our human brain and AD case-control blood transcriptomics data (and public domain data)
and identify which significant networks match to drug-signatures and/or any druggable targets. Completion of
the work proposed will enhance our understanding of the role that menopause-induced DNA damage plays in
both aging and AD. Specifically, we will: (1) elucidate the spatiotemporal relationship between DNA SSBs, DNA
methylation, and neurotrophic gene transcription in the brain during the menopause transition, (2) define a
timeline for the critic...

## Key facts

- **NIH application ID:** 10848345
- **Project number:** 5R01AG079373-03
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Claude-Henry Volmar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $458,061
- **Award type:** 5
- **Project period:** 2022-09-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848345

## Citation

> US National Institutes of Health, RePORTER application 10848345, The Role of Menopause-Driven DNA Damage and Epigenetic Dysregulation in Alzheimer s Disease (5R01AG079373-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10848345. Licensed CC0.

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