Abstract Alzheimer's disease (AD) is an irreversible neurodegenerative disorder. Among potential AD etiology, alcohol abuse and withdrawal has been suggested as a high-risk factor for AD and early-onset dementia; however, the precise mechanism by which alcohol impacts on AD pathophysiology has yet understood. Aggregation of amyloid b (Ab) peptide in the extracellular space of specific brain structures such as the hippocampus plays a causal role in the pathogenesis of AD. Although AD is increasingly viewed as a heterogeneous and multifaceted disorder, hippocampal hyperactivity and high levels of Ab secretion in the hippocampus are common signatures during early stages of AD. Recent studies from both human AD patients and familial AD (FAD) mouse models have suggested that a vicious cycle of Ab-mediated hyperactivation of the hippocampus underlies AD development and AD-related dementia (ADRD) in the preclinical stages. In response to the NOSI, we seek to understand the role of alcohol in hippocampal hyperactivity and Ab secretion. Specifically, we will test the hypothesis that 1) alcohol withdrawal (AW) induces hippocampal hyperactivity, 2) hyperactive hippocampus then increases the release and deposition of Ab, and 3) secreted Ab, in turn, contributes to hyperexcitability of hippocampus. We recently discovered that AW after chronic alcohol consumption induces non-convulsive seizures and that elevated activity of adult-born dentate gyrus cells (abDGCs) leads to hippocampal hyperactivity and seizures during a sustained period of abstinence. These observations have provided the foundation for the hypothesis that AW is a key element that initiates and aggravates a vicious cycle of Ab-mediated hyperactivation of the hippocampus via hippocampal abDGCs. In this proposal, we will test following hypotheses: 1) that hyperactivity of the hippocampus induced by AW promotes soluble Ab secretion (Aim 1) and 2) that specific inhibition of hippocampal newborn DGCs may normalize hippocampal hyperactivity and Ab secretion (Aim 2). Results from these experiments are expected to provide entirely new cellular and circuitry mechanisms by which AW following chronic alcohol exposure promotes hyperactivity of the hippocampus, the onset and progression of AD, and memory impairments. We expect to provide a foundation for developing strategies to prevent and treat AW-mediated AD pathology by modulating targeted hippocampal neural circuits. Relevance to the NOSI: The PI’s current RO1 grant seeks to understand how alcohol induces hippocampal hyperactivity and seizure development via abDGCs and does not focus on AD. Therefore, our request for administrative supplements to determine the role of AW-induced hippocampal hyperactivity in a vicious cycle of Ab-mediated hippocampal hyperactivity and AD development is within the scope of the parent research.