Summary Alzheimer's disease (AD) is a common neurodegenerative disease with progressive memory loss and cognitive decline. Early detection is critical for prevention and treatment of AD and AD related dementia (ADRD). It has been estimated that delay of the onset of dementia by even one year would reduce the prevalence of dementia by 10%. Recently, increasing evidence demonstrates that AD pathological changes can occur in sensory associated brain areas 5-10 years early before typical AD symptoms present, suggesting that they could serve as early biomarkers for AD/ADRD detection and diagnosis. Hearing is an important neural sense. Hearing loss also is a major high-risk factor for dementia. Recent studies demonstrated that visual and auditory stimulations with gamma oscillation cycles could reduce amyloid-ȕ (Aȕ expression in the brain and improve memory in AD mice. We hypothesize that hearing has a critical role in AD development and progression. However, hearing is an understudied field in AD study. Little is known about AD-induced hearing changes. Previous epidemiological studies demonstrated that AD patients could have hearing loss. However, since aged persons usually have age-related hearing loss (ARHL), it was hard to distinguish AD-induced hearing decline from ARHL in those epidemiological studies. The link to AD pathology also could not be determined and remained unclear. In this project, we will use AD mouse models to identify and characterize AD-induced functional and pathological changes in the auditory system (Aim 1). Both familial AD (fAD) and sporadic AD (sAD) mouse models will be used to increase experimental rigor. AD-induced functional changes in the auditory system will be longitudinally examined and assessed during AD development and progression. These changes will be linked to Aȕ and Tau protein expressions and genomic changes in the auditory system, which will be assessed by RNA sequencing. The AD hearing marker, thus, can be unambiguously determined. In Aim 2, we will use both AD and ARHL mouse models to further distinguish AD-induced hearing decline from ARHL. We will also define the impact of hearing loss on AD/ADRD development and progression and test whether ARHL can accelerate/exacerbate AD/ADRD development and progression. These proposed studies can improve our understanding AD pathology and the role of hearing in AD/ADRD development and progression. Such information is also critical and required for understanding the underlying mechanism for the therapeutic effect of acoustic stimulation against AD and further improving treatment and prevention.