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

Yang, S. J.; Lin, A. A.; Shen, H.; Pappalardo, L. W.; Spychalski, G. B.; Rosario, J.; Forsberg, L. K.; Grant, K. M.; Savica, R.; O'Bryant, S.; Jones, D. T.; Dickson, D. W.; Reichard, R. R.; Nguyen, A. T.; Meaney, D. F.; Boeve, B. F.; Ross, O. A.; McLean, P. J.; Issadore, D.

doi:10.1101/2025.06.06.656900

bioRxiv · 10.1101/2025.06.06.656900

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

Yang, S. J.·Lin, A. A.·Shen, H.·Pappalardo, L. W.·Spychalski, G. B.·Rosario, J.·Forsberg, L. K.·Grant, K. M.·Savica, R.·O'Bryant, S.·Jones, D. T.·Dickson, D. W.·Reichard, R. R.·Nguyen, A. T.·Meaney, D. F.·Boeve, B. F.·Ross, O. A.·McLean, P. J.·Issadore, D.

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Abstract

INTRODUCTIONRobust plasma-based biomarkers to distinguish Lewy body disease (LBD) and Alzheimers 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. METHODSWe 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 (A{beta}40, A{beta}42, tau, p-Tau181, p-Tau231) via SIMOA. RESULTSWe 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. DISCUSSIONBrain-derived EVs offer accurate and accessible miRNA biomarkers for the differential diagnosis of LBD and AD.

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Yang, S. J., Lin, A. A., Shen, H., Pappalardo, L. W., Spychalski, G. B., Rosario, J., Forsberg, L. K., Grant, K. M., Savica, R., O'Bryant, S., Jones, D. T., Dickson, D. W., Reichard, R. R., Nguyen, A. T., Meaney, D. F., Boeve, B. F., Ross, O. A., McLean, P. J., Issadore, D.. 2025-06-09. Brain-derived extracellular vesicle microRNAs in Lewy body and Alzheimer's disease. https://doi.org/10.1101/2025.06.06.656900

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