Abstract Alcohol abuse damages liver, pancreas, heart, brain, and muscle. One severe outcome of alcohol abuse is cognitive impairment and dementia. Although a role for alcohol in promoting Alzheimer's disease (AD) is suspected, the underlying mechanisms are poorly understood. One proposed underlying mechanism in AD is impaired or insufficient autophagy, an evolutionarily conserved lysosomal degradation pathway that regulates organelle and protein homeostasis. Autophagy generally declines with age, resulting in an accumulation of misfolded proteins including tau and β amyloid, as well as damaged mitochondria. Our recent work has demonstrated that alcohol induces dysfunction of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis. Impaired TFEB leads to decreased lysosomal biogenesis and mitophagy resulting in alcoholic hepatitis and pancreatitis. In addition to regulating autophagy, we also demonstrated that TFEB increased mitochondrial biogenesis by up-regulating peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α). More importantly, decreased nuclear TFEB levels is associated with human alcoholic hepatitis and pancreatitis but its role in alcohol-associated AD has not been investigated. Our preliminary results showed that alcohol decreased total and nuclear TFEB but increased ubiquitinated proteins in mouse hippocampi. In addition, aged mice (22-months old) also have decreased nuclear TFEB staining but increased p62 and phosphorylated Tau in the hippocampi compared with young mice (3-months old). These collective observations suggest that alcohol consumption and aging may synergistically interact to perturb the TFEB-lysosome biogenesis axis, thereby leading to impaired brain autophagy. Here, we hypothesize chronic alcohol consumption compounds age-related decrease of TFEB-mediated lysosomal biogenesis in the brain, which in turn leads to an accumulation of damaged mitochondria and protein aggregates. These phenomena occur in AD, and our proposed experiments promise to establish links between brain aging, alcohol consumption, and AD pathology. We further predict overexpression of TFEB and TFEB knockin transgenic mice will protect against these brain aging and alcohol-induced pathologies. We also propose to assess potential neuroprotective effects of novel TFEB agonists identified from a high-throughput screening that were recently completed. The successful completion of the proposed work will provide a new paradigm of uncovering the role of TFEB in autophagy and lysosome biology in alcohol-associated AD and brain aging.