PROJECT SUMMARY A history of heavy alcohol and a history of stress both independently increase the risk of Alzheimer's disease related dementia, including early onset dementia. We propose that high alcohol consumption facilitates the onset of, or exacerbates the severity of, Alzheimer's disease pathology specifically in the brainstem nucleus locus coeruleus (LC). The basic research that defines which aspects of Alzheimer's disease related pathology are driven by alcohol and how, remains unknown. The pathological changes that lead to Alzheimer's disease are known to occur decades before symptoms arise. One of the earliest changes in the central nervous system is tau hyperphosphorylation and cellular dysfunction within LC. LC pathology is a ubiquitous finding of post- mortem Alzheimer's disease. Given the established relationship between LC pathology and sporadic Alzheimer's disease, agents that promote pathology within LC likely promote Alzheimer's risk. In our parent grant we look at the impact of alcohol and stress on LC function in young animals, we have established that high alcohol drinking mice and monkeys also demonstrate cognitive dysfunction. The goal of this supplement is to investigate how alcohol and stress history that drives elevated drinking contributes to Alzheimer's related pathology in middle aged animals. Our central hypothesis is that elevated drinking in response to alcohol and stress history also promotes early onset Alzheimer's-like pathology in the LC. We will evaluate this hypothesis across sexes and species using rodents and non-human primates. We will investigate the relationship between alcohol dose, changes in cognition and Alzheimer's disease-like pathology in LC. We will compare age- matched controls to alcohol and stress exposed animals and look at individual differences in alcohol intake, cognition and Alzheimer's related pathology. A histopathological battery of markers will be used to evaluate LC integrity, measuring oxidative stress, autophagy, apoptosis, hyperphosphorylated tau, adrenergic receptor expression and unbiased stereological counts of LC from macaques and mice with varying alcohol dose histories. In both species we will analyze the relationship between prior alcohol intake, cognition, and pathology to identify behavioral predictors indicative of risk for Alzheimer's-like pathology. These aims will answer pressing questions on the relationship between alcohol intake and Alzheimer's disease. Cross-species analysis and markers back translated from human Alzheimer's samples enhance the clinical relevance of our findings. Our results will inform future diagnostic and early intervention strategies for Alzheimer's disease in the context of alcohol use disorder.