Project Summary and Relevance Dementia including Alzheimer’s disease (AD) is manifested in aging population, yet all the clinical trials over the years failed to halt or revise the progression of the diseases. The prevalence of the diseases increases with age and will present as ever larger burden in future given the disproportional increase in aging population worldwide. Studies have suggested an association between sensory disorders such as hearing, visual, and olfactory impairments with cognitive decline in older adults although these associations are complex and can exhibit bidirectionality. Several hypothetical mechanisms have been proposed, such as a common pathophysiology or a cause-effect relationship between sensory deficits and dementia and Alzheimer’s disease. However, it remains to be determined if and the extent to which hearing loss contributes to dementia or Alzheimer’s disease and if rescue of hearing could lessen disease phenotypes. Recently hearing loss has been hypothesized to play a role as one of the largest modifiable risk factors for dementia and Alzheimer’s disease. The availability of mouse models for hearing loss and AD makes it possible to directly evaluate if hearing loss, manifested in young or adult age, contributes to AD on the functional and structural measures. In this administration supplement, we will leverage our work in editing therapy to treat genetic deafness mouse models due to dominant mutations in the Pmca2(Atp2b2)gene and microRNA mir96 to establish if early onset hearing loss in the Pmca2 mice and progressive hearing loss in the mir96 mice contribute to AD disease phenotype in two well-characterized AD mouse models (5xFAD and 3xTg-AD, due to expression of human APP and PSEN1 transgenes). This will be done by introducing Pmca2 and Mir96 mutations into the AD background and by studying if the AD phenotypes in behavior (spatial working memory, impaired learning, cortex-dependent remote memory, fear conditioning and motor impairment) is exacerbated by hearing loss. Cellular events including astrogliosis and microgliosis, synaptic degeneration and neuron loss will also be compared. Our ongoing R01 work has demonstrated that editing therapy robustly rescues hearing in the Pmca2 mice and we have optimized sgRNA to editing the mir96 mutation to rescue hearing. By selecting hearing loss models that can be treated successfully by editing therapy, we will determine if hearing rescue leads to lessening of the progression of the AD phenotypes. The study will provide the insight into the mechanism of interactions between hearing loss and Alzheimer’s disease, and to establish the potential of personalized hearing loss therapy on the progression of Alzheimer’s disease.