Project Summary: Deficits in olfaction were recognized decades ago as early symptoms in people with incipient Alzheimer’s Disease. However, these discoveries have had less impact than hoped on the study, diagnosis, and treatment of this disease. Though central nervous system olfactory pathways suffer the plaques and/or tangles that are characteristic of late-stage disease, these symptoms do not set the olfactory system apart from other foci of research into Alzheimer’s Disease. Perhaps because the regenerative capacity of the olfactory epithelium obscured the vulnerability of olfactory sensory neurons to Alzheimer’s Disease, especially the early events leading to the neurodegeneration characteristic of the disease, study of how the olfactory epithelium is impacted by Alzheimer’s Disease languished. Clear evidence that the olfactory sensory neurons in the epithelium are susceptible to factors that cause or increase risk of Alzheimer’s Disease has recently emerged, however. These findings demonstrate that the olfactory epithelium is a worthy model of how risk factors for Alzheimer’s Disease affect neurons and their supporting cells. Thus far the data correlate well with effects in the brain, evidence that the olfactory epithelium may be a bellwether for events transpiring in the central nervous system. The accessibility of the olfactory epithelium for biopsy to assess disease progression in individuals and to drugs that cannot pass the blood brain barrier further elevates the significance of the olfactory epithelium as a model. This project investigates the effects of a critical risk factor for Alzheimer’s Disease, APOE genotype, on the olfactory epithelium and its olfactory sensory neurons. The experiments focus on identifying early events and the strength of their effects on phenotype and function. It uses mouse models of the disease, including established genetic models previously used to investigate effects in the brain and a novel model that allows switching at will from a neurodegenerative genotype to a neuroprotective genotype. The latter allows testing of whether cellular and molecular events associated with vulnerability to Alzheimer’s Disease can be prevented or reversed by in vivo genetic manipulation, outcomes that would inform and inspire further work towards curing this disease.