Uncovering the Synergistic Effects of Chronic Alcohol Use and Pathological Tau Expression

Alcohol use can accelerate the detrimental processes of aging in terms of cognitive, physical, and emotional outcomes and has been identified as the strongest modifiable risk factor for the development of Alzheimer’s Disease and Related Dementias (ADRD). Common biological mechanisms such as inflammation, amyloid-β deposition, and cell death have been observed in patients with ADRD and those who consume high amounts of alcohol in a chronic fashion. Despite evidence of this causal link, minimal focus has been placed on understanding synergistic interactions of alcohol, aging, and tau-driven neurodegeneration; which is a hallmark of multiple neurodegenerative disorders. Preclinical models of pathological tau expression, such as the PS19 tau mouse model, have been well characterized in the study of ADRD but have rarely been utilized to study consequences of chronic alcohol consumption. The prevalence of alcohol consumption in older adults is increasing and our society is aging, leaving our population even more vulnerable to the neurodegenerative effects of alcohol. Thus, the study of the intersection of aging and alcohol is more urgent than ever. The current literature on this topic is limited, so it will be critical to determine foundational knowledge about the chronic effects of alcohol in a model of neurodegeneration. The current proposal therefore aims to investigate the progression of behavioral impairment, the time course of aging-related biomarkers, and development of neurodegeneration as a result of alcohol intake and development of tau pathology. Behavioral and cognitive impairment is a critical standard that we will measure as an outcome, as it is a common feature present in pathological aging and neurodegenerative diseases. Peripheral biomarkers represent a method of quantifying the level of biological impairment and assessing the overall state of aging and degeneration in multiple systems across the body. All of the biomarkers we have selected to measure in this proposal have a parallel clinical assessment that can be measured noninvasively, which will be beneficial for translational purposes. SPECIFIC AIMS: (1a) Determine how voluntary chronic alcohol intake in the presence of pathological tau expression impacts behavioral and aging-related outcomes across the lifespan, (1b) Delineate the synergistic effects of specific low or high alcohol intake and pathological tau expression, (1c) Utilize machine learning techniques to predict behavioral and neurological outcomes from acute biomarker measures, and (2) Investigate the acute effects of alcohol in a mouse model of tauopathy. The successful completion of this proposal will provide a holistic characterization of how aging is affected by alcohol over the lifespan, highlight new biomarkers to predict chronic adverse outcomes, and ultimately provide potential clinical targets to combat physical, emotional, and cognitive impairments in the aging population.