SUMMARY Alzheimer’s disease (AD) is the most common form of dementia with an estimated 6.5 million patients aged 65 and older being affected in the US. Current FDA-approved therapies for AD include anti-amyloid antibody infusion therapy to delay disease onset or cholinesterase inhibitors and glutamate regulators to treat cognitive symptoms. However, these treatment options carry severe side effects and are not effective at stabilizing cognitive symptoms or curing the disease. Collectively, these observations underscore an unmet medical need for novel targets that allow for efficacious eradication of the neurodegenerative features and symptoms related to AD. Interestingly, AD patients are known to also suffer from deficits in somatosensory perception, including our sense of gentle touch. However, these deficits are postulated to be masked by the severe cognitive dysfunction observed in the AD brain. Nevertheless, our sense of gentle touch enables numerous behaviors fundamental to human existence, allowing us to eat, communicate and survive and is encoded by cutaneous Merkel cells, a mature neuroendocrine lineage of mechanoreceptors that are innervated by slowly adapting type I afferents. The overarching goal of our active R01AG073874 grant is to define the cellular and molecular basis for maintenance of the Merkel lineage in the adult skin and leverages key preliminary data from our laboratory that comprehensively chronicles a dramatic decline in Merkel cell numbers and tactile acuity in human and murine skin across the lifespan. Since aging is a risk factor for AD onset and deficits in tactile acuity, and somatosensory deficits, including loss of gentle touch, are a reported co-morbidity in AD patients, we postulated that convergent mechanisms may govern these pathologies in the central nervous system (AD) and the periphery (Merkel cells). In support of this idea, our new preliminary data shows i) highly accelerated loss of cutaneous Merkel cells in four-month-old 5XFAD transgenic mice, a widely utilized mouse model of AD, and ii) expression enrichment for two AD-associated proteins, App and Psen1, in epithelial progenitors for the Merkel lineage. Collectively, these observations raise the hypothesis that AD-related mutations harbored in 5XFAD mice may also be relevant for Merkel cell stability. We will test this hypothesis with a comprehensive assessment of the impact of AD mutations on Merkel cell numbers and epithelial progenitor function in the skin. Our preliminary data also highlight the need to leverage 5XFAD mice to identify putative convergent mechanisms of disease etiology between age-associated AD and Merkel cell loss. We will address this need by creating a multi-omics atlas of AD at single-cell resolution in brain and skin tissues at critical age points across the murine lifespan correlating with pre- and post-AD onset in humans. These efforts will support our long-term goal to uncover rare cell types with unknown markers of AD and o...