Brain-Derived Tau Oligomers in Circulating Extracellular Vesicles as Predictive Biomarkers for Alzheimer’s Disease Conversion

Sep 30, 2026

Uploaded by Levi

Background: Alzheimer’s disease requires reliable predictive biomarkers for early identification in the preclinical stage. Blood-based markers, including plasma brain-derived extracellular vesicles (pl-BDEVs), have shown value for detecting central nervous system changes, yet predictive biomarkers remain insufficient. Method: pl-BDEVs were enriched from longitudinal plasma in TARCC cohorts, separating converters from non-converters. Nanoparticle tracking, western blot (CD63/CD9/CD81), and electron microscopy characterized vesicles, followed by immunoprecipitation of brain-derived tau oligomers (BDTOs) and assessment by western blot, PK digestion, seeding assay, and AFM, with SH-SY5Y and synaptosome toxicity tests. Results: BDTOs were detected in pl-BDEVs, showing distinct PK digestion patterns, morphology, toxicity, and distribution between groups. Conclusion: Distinct BDTO strains suggest a predictive peripheral biomarker route.

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CategoryHealthcare

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Abstract

Background

Method

Results

Conclusion

DOI: 10. 1002/alz70856_106869 BIOMARKERS POSTER PRESENTATION BIOMARKERS (NON-NEUROIMAGING) Brain-Derived Tau Oligomers in Circulating Extracellular Vesicles as Predictive Biomarkers for Alzheimer’s Disease Conversion Michela Marcatti Anna Fracassi Wenru Zhang Rakez Kayed Giulio Taglialatela University of Texas Medical Branch, Galveston, TX, USA Correspondence Michela Marcatti, University of Texas Medical Branch, Galveston, TX, USA. [Email:](Email: mimarcat@utmb.edu)[ mimarcat@utmb.edu](Email: mimarcat@utmb.edu) Abstract Background: Alzheimer’s disease (AD) is one of the most common forms of dementia worldwide, making the identification of predictive biomarkers critical for early diagnosis and treatment during the preclinical stage. Recent studies have focused on blood-based biomarkers, particularly plasma brain-derived extracellular vesicles (pl-BDEVs), to detect central nervous system (CNS) alterations. While blood biomarkers like amyloid proteins (Aβ42/Aβ40), tau, and phosphorylated tau show diagnostic promise, identifying predictive biomarkers remains essential. Blood total-tau, originating from non-brain sources, highlights the need to analyze brainderived tau (BDT) in pl-BDEVs as a more specific biomarker for AD and other neurodegenerative diseases. Longitudinal studies offer great potential for detecting preclinical biomarker patterns in at-risk individuals, yet little attention has been given to oligomers, the most toxic species in AD Method: In this study, we enriched pl-BDEVs from CNS cell types from plasma samples longitudinally collected from participants enrolled in the Texas Alzheimer’s Research and Care Consortium (TARCC), who were initially cognitively normal or displayed mild cognitive impairment (MCI), and later either progressed to AD (termed “converters”) or remained cognitively normal/MCI (termed “non-converters”). We evaluated the isolated pl-BDEVs by nanoparticle tracking analysis (size, number, and distribution), western blot (expression of extracellular vesicles markers: CD63, CD9, CD81), and electron microscopy. We immunoprecipitated brain-derived tau oligomers (BDTOs) from pl-BDEVs and characterized them by western blot, proteinase K (PK) digestion, seeding assay, and atomic force microscopy (AFM). Additionally, we treated SH-SY5Y neuroblastoma cells and human synaptosomes isolated from cortex of control samples with these BDTOs and assessed their cytotoxicity and synaptotoxicity, respectively. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2025 The Alzheimer’s Association. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association. Alzheimer’s Dement. 2025;21(Suppl. 2):e106869. [https://doi.org/10.1002/alz70856_106869](https://doi.org/10.1002/alz70856_106869) wi[leyonlinelibrary.com/journal/alz](leyonlinelibrary.com/journal/alz) 1of2 BIOMARKERS Result: We demonstrated the successful isolation of pl-BDEVs from plasma samples and the detection of BDTOs within these pl-BDEVs. We identified distinct PK digestion patterns, morphology, and toxicity between BDTOs from converters and non-converters. Additionally, our data revealed different distribution of BDTOs in the pl-BDEVs isolated from the two groups. These findings suggest the presence of two different BDTO strains for converters and non-converters. Conclusion: This study addresses the need for predictive AD biomarkers by analyzing previously unexplored BDTO conformers in pl-BDEVs. Discovering distinct BDTOs in peripheral brain derived extracellular vesicles could enable preclinical forecasting and advance early-stage AD treatments.

FAQs

Why are predictive biomarkers important in Alzheimer’s disease conversion?

The document states that identifying predictive biomarkers is critical for early diagnosis and treatment during the preclinical stage, enabling detection of individuals likely to convert to Alzheimer’s disease.

How were plasma brain-derived extracellular vesicles (pl-BDEVs) and BDTOs studied?

pl-BDEVs were enriched from longitudinal plasma samples, characterized by nanoparticle tracking analysis, western blot for vesicle markers (CD63/CD9/CD81), and electron microscopy. Brain-derived tau oligomers were immunoprecipitated from pl-BDEVs and characterized by western blot, proteinase K digestion, seeding assay, and atomic force microscopy.

What differences were observed between converters and non-converters?

The study found distinct PK digestion patterns, morphology, toxicity, and different distributions of BDTOs in pl-BDEVs between converters and non-converters, suggesting different BDTO strains.

Sep 30, 2026

Uploaded by Levi