Effects of a-synuclein pathology on synaptic dysfunction and clinical outcomes in normal aging.

Effects of a-synuclein pathology on synaptic dysfunction and clinical outcomes in normal aging. Alzheimer's & dementia : the journal of the Alzheimer's Association Winer, J. R., Plastini, M. J., Romero, A., Vossler, H., Sai, I., Channappa, D., Abdelnour, C., Shahid-Besanti, M., Wilson, E. N., Oh, H. S., Young, C. B., Trelle, A., Yutsis, M., Sha, S. J., Ramirez, V., Taylor, R., Younes, K., Wyss-Coray, T., Greicius, M. D., Henderson, V. W., Wagner, A. D., Poston, K. L., Mormino, E. C. 2026; 22 (5): e71455

Abstract

a-Synuclein is the hallmark pathology of Parkinson's disease and dementia with Lewy bodies, described together as Lewy body disease (LBD). We investigated effects of a-syn biomarker positivity in clinically unimpaired (CU) individuals.We assessed a-syn status (a-syn ±) in 269 CU individuals using a cerebrospinal fluid (CSF) seed amplification assay (SAA). Fifty-six participants with AD and 85 LBD spectrum participants were included for comparison. We compared a-syn SAA results with demographics, fluid biomarkers, cognitive performance, and clinical measures.a -Syn positivity was detected in 9% of CU individuals, a lower rate than in clinically impaired participants with AD (16%) and LBD diagnoses (81%). Compared to a-syn-, a-syn+ CU individuals were older, showed lower synaptic integrity, performed worse on tests of executive function and working memory, and reported more LBD-related non-motor symptoms.Further work is needed to understand the timeline of neural and clinical changes in a-syn+ CU individuals and heterogeneity in disease progression.

View details for DOI 10.1002/alz.71455

View details for PubMedID 42071168

View details for PubMedCentralID PMC13135916