PROJECT SUMMARY Alzheimer’s disease (AD) is a large and growing worldwide public health epidemic. Because there is no cure for AD, much clinical effort is focused on interventions targeting potentially modifiable risk factors. Recent epidemiological studies have identified hearing loss (HL) as a major modifiable risk factor for AD. These findings have prompted debate over whether HL specifically accelerates AD pathology, or if the link instead reflects shared risk factors such as age, genetics, or metabolic conditions. Because human studies are necessarily correlational, an animal model is necessary to determine whether HL specifically influences AD pathology. We address this question in Aim 1 using the E4FAD mouse model of AD, which is homozygous for the most prevalent genetic AD risk factor (ApoE4) and co-expresses five additional familial AD mutations. We will determine whether HL induced by cochlear ablation accelerates AD pathology, including hallmark accumulations of amyloid β (Aβ) as plaques and phosphorylated tau (p-tau), as well as increased neuronal hyperactivity and reductions in memory-related sharp wave ripples (SWRs). Because these pathologies emerge first within entorhinal cortex (EC) and hippocampus (HC), we will assess cognitive impairment (CI) reflecting EC-HC dysfunction (e.g., spatial memory). The expected results will be informative for clinical best practices, e.g., by suggesting whether prevention and treatment of HL could itself mitigate AD, or if instead targeting a common cause is needed to address both HL and AD. Independent of these outcomes, recent studies in rodents have shown HL causes long lasting CI reflecting HC dysfunction. Although the underlying mechanisms remain poorly understood, they may include side effects of noise exposure in rodents (e.g., elevated stress hormones in HC), as well as psychosocial factors in humans (e.g., communication difficulty and social withdrawal). However, recent rodent studies have documented CI following HL induced without noise exposure (e.g., cochlear ablation), implicating mechanisms other than psychosocial factors and noise side effects. A leading candidate mechanism in such cases is disrupted neuronal activity in the EC-HC which could result from altered input from the auditory pathway following HL (e.g., decreased sound-related activity and increased spontaneous hyperactivity). We address this possibility in Aim 2 through longitudinal physiology recordings in EC-HC and auditory cortex (ACtx) before and after HL induced by cochlear ablation. We will examine whether hyperactivity emerges in EC-HC in parallel with upstream ACtx, quantify possible reductions in SWRs, and determine whether functional connectivity is altered between EC-HC and ACtx. The expected results will clarify mechanisms of HL-induced CI and may suggest clinical responses to both HL and CI (e.g., pharmacological attenuation of hyperactivity). Collectively, our proposal will resolve outstanding unresolved ques...