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

Alzheimer's & dementia : the journal of the Alzheimer's Association
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Joseph R Winer, Melanie J Plastini, America Romero, Hillary Vossler, Isha Sai, Divya Channappa, Carla Abdelnour, Marian Shahid-Besanti, Edward N Wilson, Hamilton Se-Hwee Oh, Christina B Young, Alexandra Trelle, Maya Yutsis, Sharon J Sha, Veronica Ramirez, Ryan Taylor, Kyan Younes, Tony Wyss-Coray, Michael D Greicius, Victor W Henderson, Anthony D Wagner, Kathleen L Poston, Elizabeth C Mormino

Alzheimers Dement. 2026 May;22(5):e71455. doi: 10.1002/alz.71455.

ABSTRACT

INTRODUCTION: α-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 α-syn biomarker positivity in clinically unimpaired (CU) individuals.

METHODS: We assessed α-syn status (α-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 α-syn SAA results with demographics, fluid biomarkers, cognitive performance, and clinical measures.

RESULTS: α -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 α-syn-, α-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.

DISCUSSION: Further work is needed to understand the timeline of neural and clinical changes in α-syn+ CU individuals and heterogeneity in disease progression.

PMID:42071168 | PMC:PMC13135916 | DOI:10.1002/alz.71455