Brain-derived extracellular vesicle microRNAs in Lewy body and Alzheimer’s disease

  1. Stephanie J. Yang
  2. Andrew A. Lin
  3. Hanfei Shen
  4. Laura W. Pappalardo
  5. Griffin B. Spychalski
  6. Jean Rosario
  7. Leah K. Forsberg
  8. Kiera M. Grant
  9. Rodolfo Savica
  10. Sid O’Bryant
  11. David T. Jones
  12. Dennis W. Dickson
  13. R. Ross Reichard
  14. Aivi T. Nguyen
  15. David F. Meaney
  16. Bradley F. Boeve
  17. Owen A. Ross
  18. Pamela J. McLean
  19. David Issadore
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Abstract

INTRODUCTION

Robust plasma-based biomarkers to distinguish Lewy body disease (LBD) and Alzheimer’s disease (AD) are currently lacking. We applied track-etch magnetic nanopore (TENPO) sorting for enrichment of brain-derived extracellular vesicle (EV) signatures as potential biomarkers to address this gap.

METHODS

We analyzed plasma from 137 autopsy-confirmed patients [30 LBD, 31 AD, 30 AD/LBD, 19 AD with amygdala Lewy bodies (AD/ALB), and 27 controls], sequencing miRNAs from TENPO-isolated GluR2-positive (neuron-enriched) and GLAST-positive (astrocyte-enriched) EVs, and measuring plasma proteins (Aβ40, Aβ42, tau, p-Tau181, p-Tau231) via SIMOA.

RESULTS

We identified 16 GluR2+, 8 GLAST+, and 4 protein biomarkers with differential expression (false discovery rate-corrected P value < .1) between LBD and AD. A multimodal 15-feature panel classified LBD versus AD with 10-fold cross-validated accuracy = 0.95 and area under the curve (AUC) = 0.96.

DISCUSSION

Brain-derived EVs offer accurate and accessible miRNA biomarkers for the differential diagnosis of LBD and AD.

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  1. Version published to 10.1101/2025.06.06.656900 on bioRxiv