Project Summary/Abstract Hearing loss is a significant risk factor for dementia, including the most common form of CNS degenerative disorder, Alzheimer’s disease (AD). Despite strong association, the cause-effect relationship between auditory dysfunction and AD is unknown. Moreover, AD pathology can potentially affect the outcome of a cochlear implant (CI), an auditory prosthesis that provides rehabilitation for patients with the most severe forms of hearing loss. Based on preliminary data from CI patients and mouse models of AD, we hypothesize that the neuropathological processes, including inflammation, that lead to CNS neurodegeneration in AD also impact the response of the auditory nerve to acoustic and electrical stimulation. To test this hypothesis, Aim 1 uses a CI system we recently developed to provide long-term electrical stimulation in mice to characterize the electrophysiological function of the cochlea and auditory nerve in a mouse models of AD (5XFAD and AppNL-G- F) after cochlear implantation. In a second aim we explore the hypothesize that the heighten neural inflammatory state of AD mouse models will exacerbate inflammation and fibrosis in the cochlea following CI. Hair cell counts, spiral ganglion neuron survival, and macrophage infiltration to the scala tympani, lateral wall and spiral ganglia will be quantified. Fibrosis and neo-ossification in the scala tympani will be quantified using 3D X-ray microscopy and confirmed by -smooth muscle actin immunoreactivity. Taken together, these studies will rigorously establish the electrophysiological and histopathological consequences of AD-related neuropathologies on the auditory nerve and its ability to respond to electrical stimulation. Future studies will expand the findings from this work to other mouse models of AD and will also explore these findings in our large cohort of human CI recipients.