Presentation Details
| Alzheimer’s pathobiology detection prior to symptom onset via olfactory biopsy analysis Vincent M D'Anniballe1, Bradley J Goldstein2. 1Duke Medical Scientist Training Program, Duke University School of Medicine, Durham, NC, USA.2Department of Head and Neck Surgery & Communication Sciences, Duke University School of Medicine, Durham, NC, USA |
Abstract
Early detection of Alzheimer’s disease (AD) before cognitive decline remains a critical unmet need. Current diagnostics rely on amyloid-β and p-tau measurements in plasma or cerebrospinal fluid, rather than direct interrogation of living neuronal tissue. This limitation may obscure early pathogenic mechanisms, constrain functional assays, and contribute to ongoing debate regarding the biological relevance of observed pathology. Similar to cortical neurons at advanced disease stages, olfactory sensory neurons (OSNs) in the nasal olfactory epithelium (OE) accumulate hallmark AD pathology. However, whether detectable pathobiology impacts the peripheral OE at an early, pre-clinical stage has remained unclear. We performed endoscopically guided OE brush biopsies in adults classified by 2024 Alzheimer’s Association biomarker criteria as controls (n=6), asymptomatic pre-clinical AD (n=9), or clinical AD (n=6). Single-cell RNA sequencing profiled live OE cells using experimentally validated gene expression programs, flow cytometry provided orthogonal validation. Strikingly, pre-clinical OSNs exhibited inflammatory programs previously described in postmortem AD cortical neurons. OE myeloid cells adopted an inflammatory, microglia-like state that intensified with disease progression. Concurrently, OE CD8⁺ memory T cells exhibited elevated antigen-specific activation scores in pre-clinical AD compared with controls, mirroring cerebrospinal fluid T cell activation in clinical AD, and confirmed by increased CD38⁺HLA-DR⁺CD8⁺ T cells by flow cytometry. Together, these findings support OE brush biopsies as a minimally invasive approach to capture neuronal and immune signatures of AD prior to cognitive impairment, supporting use for early detection and mechanistic discovery.
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No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.