# Alcohol-Induced Metabolome-Epigenome Dysfunction and Alzheimer's Disease Risk

> **NIH AA K99** · UNIVERSITY OF FLORIDA · 2026 · $148,985

## Abstract

PROJECT SUMMARY / ABSTRACT
Epidemiological projections indicate a substantial rise in Alzheimer's disease (AD) cases, reaching an
estimated 152 million by 2050. Among the multifaceted factors influencing AD progression, chronic alcohol
consumption is implicated as a modifiable risk factor for AD. My long-term goal is to uncover mechanisms that
contribute to the risk of developing early progression of AD upon alcohol consumption and develop therapeutic
interventions to mitigate this risk. While recent studies indicate metabolic disorders and accelerated aging in
individuals with Alcohol Use Disorder (AUD), energy metabolism emerged as a significantly altered pathway
triggering early AD pathology. This project employs an interdisciplinary approach to understand the impact of
alcohol on the brain, with a specific focus on elucidating the complex relationship between metabolic and
epigenetic function. The overall objective of this study is to comprehend how these factors collectively
contribute to the progression of AD following ethanol exposure. In Specific Aim 1, I will assess the influence of
chronic ethanol exposure on metabolic function and tau pathology in the hippocampus using an AD model
(rTg4510) expressing the mutant human tau MAPTP301L. Specific Aim 2 involves applying cutting-edge
techniques, such as single nuclei multi-omics, to identify cell-type-specific epigenomic and transcriptomic
signatures associated with alcohol-induced early progression of tau pathology. The focus of Specific Aim 3 is
on creating a novel mouse model (rTg4510-ALDH2*2) expressing both human genetic mutations, ALDH2E504K
and MAPTP301L to assess compromised metabolism and its impact on early AD progression. Additionally, we
will investigate the potential rescue from ethanol-induced tauopathy and cognitive deficits using a
pharmacological ALDH2 activator (Alda-1). The innovative findings from this study are expected to reveal the
molecular signatures governing the detrimental effects of

## Key facts

- **NIH application ID:** 11324876
- **Project number:** 5K99AA032034-03
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Nagalakshmi  Balasubramanian
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** AA
- **Fiscal year:** 2026
- **Award amount:** $148,985
- **Award type:** 5
- **Project period:** 2025-09-05T00:00:00 → 2027-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11324876

## Citation

> US National Institutes of Health, RePORTER application 11324876, Alcohol-Induced Metabolome-Epigenome Dysfunction and Alzheimer's Disease Risk (5K99AA032034-03). Retrieved via AI Analytics 2026-06-25 from https://api.ai-analytics.org/grant/nih/11324876. Licensed CC0.

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