Biopsy-based single cell assays for olfactory sensory changes in an Alzheimer's Disease cohort

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.