Evaluation of blood‐based, extracellular vesicles as biomarkers for aging‐related TDP‐43 pathology

INTRODUCTION: Limbic predominant age related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is a recently characterized brain disease that mimics Alzheimer's disease (AD) clinically. To date, 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. METHODS: TDP‐43 was evaluated in neuronal (NDEVs), astrocyte (ADEVs), and microglial derived extracellular vesicles (MDEVs). EV preparations were isolated from the plasma of research subjects 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 with diagnoses other than LATE‐NC (n = 42). RESULTS: TDP‐43 was significantly elevated in plasma ADEVs derived from autopsy confirmed 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. DISCUSSION: Blood‐based EVs, specifically measuring TDP‐43 accumulation in ADEVs, may serve as a potential diagnostic tool to rapidly identify subjects who are currently living with LATE‐NC.