Project Grant F30AG104439

THE OLFACTORY EPITHELIUM AS A MINIMALLY INVASIVE WINDOW INTO CNS IMMUNITY AND EARLY ALZHEIMER'S DISEASE PATHOBIOLOGY - THE OLFACTORY EPITHELIUM AS A MINIMALLY INVASIVE WINDOW INTO CNS IMMUNITY AND EARLY ALZHEIMER'S DISEASE PATHOBIOLOGY ANOSMIA IS A PRODROMAL CLINICAL FEATURE OF ALZHEIMER'S DISEASE (AD), HIGHLIGHTING THE NASAL OLFACTORY EPITHELIUM (OE) AS A POTENTIAL WINDOW INTO EARLY DISEASE BIOLOGY. THE OE CAN BE SAFELY BIOPSIED IN THE OUTPATIENT CLINIC AND THEREFORE PROVIDES RARE ACCESS TO NEURAL TISSUE IN LIVING PATIENTS WITH AD. WHILE THE OE IS KNOWN TO HARBOR EARLY AMYLOID-B AND PTAU PATHOLOGY, IT REMAINS UNKNOWN WHETHER THIS ACCESSIBLE NEURAL TISSUE ALSO RECAPITULATES THE NEUROINFLAMMATION CHARACTERISTIC OF AD PROGRESSION. PRELIMINARY SINGLE-CELL DATA FROM OUR GROUP SHOW THAT HUMAN OE T CELLS IN BIOMARKER-DEFINED, PRE-CLINICAL AD SUBJECTS EXHIBIT ACTIVATION PROGRAMS CONVERGENT WITH THOSE FOUND IN CEREBROSPINAL FLUID (CSF) FROM INDIVIDUALS WITH ADVANCED AD, SUGGESTING THAT THE OE MAY REGISTER CNS-LINKED IMMUNE ACTIVITY BEFORE COGNITIVE DECLINE. THIS PROJECT WILL TEST THE HYPOTHESIS THAT THE OE MIRRORS CNS IMMUNITY AND THAT ITS COORDINATED IMMUNE-NEURONAL TRANSCRIPTIONAL PROGRAMS ENCODE INFORMATION SUFFICIENT TO STAGE AD. WE WILL INTEGRATE PATIENT-MATCHED OE AND CSF SINGLE-CELL TRANSCRIPTOMIC, T CELL RECEPTOR (TCR)-SEQ, AND FLOW CYTOMETRY DATA TO QUANTIFY CLONOTYPE OVERLAP AND IMMUNE-STATE CONVERGENCE ACROSS COMPARTMENTS, AND CONTEXTUALIZE THESE SIGNATURES USING PUBLICLY AVAILABLE PERIPHERAL BLOOD SINGLE-CELL AND TCR DATASETS IN AD AND RELATED NEUROINFLAMMATORY DISEASES. USING CONSENSUS NON-NEGATIVE MATRIX FACTORIZATION (CNMF), WE WILL DERIVE REPRODUCIBLE IMMUNE AND NEURONAL GENE MODULES THAT CLASSIFY DISEASE STAGE AND IDENTIFY CANDIDATE GENE PROGRAMS THAT PROPAGATE ALONGSIDE HALLMARK AD PATHOLOGY. BY DEMONSTRATING EARLY AD INVOLVEMENT IN THIS ACCESSIBLE NEURAL TISSUE, THE PROPOSED WORK POSITIONS THE OE AS A MINIMALLY INVASIVE PLATFORM FOR MECHANISTIC DISCOVERY AND NEUROINFLAMMATORY MONITORING IN AD, AN APPROACH THAT COULD BE APPLIED TO OTHER NEUROINFLAMMATORY DISORDERS. THE F30 TRAINING PLAN PROVIDES THREE YEARS OF INTEGRATED DEVELOPMENT IN OLFACTORY BIOLOGY, SINGLE-CELL ANALYSIS, AND HUMAN-SUBJECTS RESEARCH PREPARING THE FELLOW FOR AN INDEPENDENT TRANSLATIONAL PHYSICIAN-SCIENTIST CAREER. THIS WORK WILL OCCUR IN DUKE UNIVERSITY'S COLLABORATIVE ENVIRONMENT, WITH MULTIDISCIPLINARY MENTORSHIP, STATE-OF-THE-ART GENOMICS AND HUMAN TISSUE PROFILING CORES, AND A ROBUST PHYSICIAN- SCIENTIST TRAINING INFRASTRUCTURE THAT TOGETHER WILL ENHANCE THE IMPACT OF THE PROPOSED RESEARCH AND TRAINING.