Levels of TDP‐43 from Plasma‐Derived Astrocyte Exosomes Accurately Differentiates Autopsy Verified LATE from AD

• Published in: Alzheimer's & dementia Vol. 19; no. S14
• Main Authors: Rissman, Robert A, Winston, Charisse N., Sukreet, Sonal, Lynch, Haley M, Lee, Virginia M. M.‐Y., Wilcock, Donna M., Nelson, Peter T.
• Format: Journal Article
• Language: English
• Published: 01.12.2023
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.078052

Background Limbic predominant age related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is a neurodegenerative disease characterized brain disease that mimics Alzheimer’s disease (AD) clinically. LATE‐NC is difficult to diagnose antemortem using clinical information or biomarkers. Recent studies suggest concentrations of extracellular vesicle (EVs) protein cargo derived from neuronal and glial cells may serve as useful diagnostic biomarkers for AD and other neurodegenerative diseases. We developed a high throughout bioassay to detect TDP‐43 in plasma derived exosomes for identification of LATE and AD. Method TDP‐43 was isolated from neuronal (NDEVs), astrocyte (ADEVs), and microglial derived extracellular vesicles (MDEVs) using antemortem plasma from participants with autopsy‐confirmed diagnoses, including many with LATE (n = 22). Quantified TDP‐43 concentrations were compared to the cohort that included healthy controls, mild cognitively impairment (MCI), and AD dementia (n = 42). Result TDP‐43 was significantly elevated in plasma ADEVs derived from LATE‐NC subjects, with or without comorbid AD pathology. Measurable levels of TDP‐43 were also detected in EV‐depleted plasma; however, TDP‐43 levels were not significantly different between persons with and without eventual autopsy confirmed LATE‐NC. No correlation was observed between EV TDP‐43 levels with cognition‐based variables, sex, and APOE carrier status. Conclusion Our recently developed bioassay and levels of TDP‐43 in ADEVs may serve as a potential diagnostic tool to rapidly identify subjects with LATE‐NC for screening into clinical trials.