PROJECT SUMMARY MAIN 2 Excessive alcohol use can increase the risk of alcohol-related brain damage and cognitive decline, including an increased risk for the development of dementia. Converging data from human studies and preclinical animal models have revealed that extreme alcohol binge drinking/exposure during adolescence is associated with long-term changes in brain structure and connectivity. Persistent brain damage after adolescent intermittent ethanol exposure (AIE) in rodents, a model of binge drinking, entails reduced hippocampal neurogenesis, suppression of the cholinergic neuronal phenotype, and alterations in the ratio between pro and mature neurotrophins. This brain profile is also seen in patients with Alzheimer’s Disease and Related Dementias (ADRD), as well as in preclinical models of such disorders. Subclinical neuropathology and/or alteration in neurotrophins following AIE likely makes the brain more vulnerable to the aging process, and normal compensatory aging responses may fail, leading to the behavioral sequelae of dementia. The goal of this proposal is to reveal how intermittent alcohol exposure during adolescence alters the normal age-related trajectory (loss of cholinergic phenotype, reduced neurogenesis) in the F344 rat, as well as the onset of additional AD-pathological markers (plaque load, hyper tau phosphorylation,) in the TgF344-AD model. Specifically, we will (a) reveal AIE-induced sex-specific neurotrophic mediators of resilience and susceptibility to compromised cognitive aging and AD-related pathology (AIM 1); (b) rescue sex-specific AIE-induced acceleration of pathological age-related cognitive decline and AD pathology by inhibiting the p75NTR cell death pathway (AIM 2). Finally, we will determine if exercise load drives the sex-dependent recovery of AIE/AD-associated spatial memory impairment and neuropathology (AIM 3). Our preliminary data revealed a profile that AIE accelerates age-related cognitive impairment in male rats, and amplifies pathological aging in female rats with AD transgenes. Ultimately, this proposal will d etermine the sex-specific drivers of accelerated age-related pathology associated with alcohol use disorders to inform effective therapeutic approaches to halt the progressive development of dementia.