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