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

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 ethanol metabolism and their involvement in the
progression or early development of AD. This, in turn, will lay the foundation for novel therapeutic approaches
aimed at mitigating the risk of developing AD due to alcohol consumption. This project provides training in
cutting-edge research skills, including single-nuclei multi-omics, and tailors toward understanding cell-type
specific tau pathology. The University of Iowa is home to experts on neuropathology, Alzheimer’s disease,
computational psychiatry, and molecular biology and offers an ideal collaborative environment for obtaining the
necessary skills to transition into a successful independent research career. During the mentored (K99) phase,
I will engage in activities designed to prepare for independence, including training in scientific presentations,
laboratory management skills, grant writing, scientific peer-review, and interview preparation. This award will
collectively equip me with cutting-edge skills and expertise in metabolic phenotyping, molecular biology, and
tauopathy, ensuring a strong technical and conceptual foundation for starting my independent laboratory
investigating mechanisms for the treatment of alcohol misuse and Alzheimer’s disease.

Grant Number: 5K99AA032034-03
NIH Institute/Center: NIH
Principal Investigator: Nagalakshmi Balasubramanian