Project Summary/Abstract A loss of olfaction, termed anosmia, is strongly associated with Alzheimer’s Disease (AD) and often precedes the development of cognitive decline or other symptoms. Currently, we lack disease-modifying treatments for olfactory disorders or for AD. Mechanisms driving olfactory loss in preclinical AD, and its relationship to disease progression, remain unclear. To gain insights into the molecular and cellular mechanisms by which sensory system changes underlie the pathogenesis of AD, we will apply newly developed approaches to analyze human olfactory cells. We will perform olfactory function testing and obtain minimally invasive olfactory biopsies from pre-clinical or symptomatic Alzheimer’s subjects, leveraging a newly developed Alzheimer’s Disease Research Center at Duke/University of North Carolina. Samples will be processed for single cell RNA- sequencing (scRNA-seq), generating a series of data sets to be shared with the field. Using our established normal or hyposmic human olfactory single cell data sets, as well as new controls, we will compare transcriptional profiles in olfactory neurons, neuron progenitors, and associated supporting populations in early or later stages of disease. We will include clinical metadata such as sex, race and APOE-e4 status to permit sub-group analyses. Finally, we will focus attention to olfactory immune cells, as neuroinflammation is a prominent aspect of both non-AD olfactory disorders as well as AD pathogenesis. Defining the immune cell population changes in early or later disease stages and the gene expression changes in these cells, we will also perform functional tests on olfactory cells using in vitro assays. An advantage of our approach will be the ability to evaluate neural tissue from well-characterized human subjects at early or later disease stages, rather than animal models or post-mortem samples. Together, completion of these studies will identify mechanistic insights into the pathogenesis of olfactory dysfunction as well as AD progression.

Project Narrative A loss of smell is associated strongly with pre-clinical Alzheimer’s Disease, yet the relationship between olfactory loss and disease progression are not understood. We have developed an approach to obtain human olfactory biopsies for single cell profiling, providing a means to directly compare neuroepithelial samples at any disease stage, focusing on sensory, supporting and immune cells. In our proposed studies, we will use this approach leveraging an Alzheimer’s Disease Research Center cohort to identify mechanistic insights into human olfactory loss as well as Alzheimer’s Disease progression.