Effects of α‐synuclein pathology on synaptic dysfunction and clinical outcomes in normal aging
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.
Authors
- America Romero
- Carla Abdelnour (ORCID: https://orcid.org/0000-0002-7636-9758)
- Kyan Younes (ORCID: https://orcid.org/0000-0002-9912-1616)
- Isha Sai
- Ronald C. Taylor (ORCID: https://orcid.org/0000-0001-9777-9767)
- Hamilton Se‐Hwee Oh (ORCID: https://orcid.org/0000-0001-8192-7593)
- Melanie J. Plastini (ORCID: https://orcid.org/0000-0003-2011-7882)
- Divya Channappa
- Sharon J. Sha (ORCID: https://orcid.org/0000-0002-3666-1463)
- Joseph R. Winer (ORCID: https://orcid.org/0000-0003-4069-3158)
- Michael D. Greicius (ORCID: https://orcid.org/0000-0002-5462-9037)
- Elizabeth C. Mormino (ORCID: https://orcid.org/0000-0002-4542-6537)
- Marian Shahid (ORCID: https://orcid.org/0000-0002-8515-3238)
- Christina B. Young (ORCID: https://orcid.org/0000-0001-9535-2137)
- Hillary Vossler
- Tony Wyss-Coray
- Maya Yutsis
- Veronica Ramirez
- Kathleen L. Poston
- Anthony D. Wagner
- Edward N. Wilson
- Victor W. Henderson
- Alexandra Trelle
Institutions
- Allen Institute for Brain Science (US)
- Neurosciences Institute (US)
- Stanford Health Care (US)
- Stanford Medicine (US)
- University of California, Davis (US)
- Stanford University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Alzheimer s & Dementia
- Published
- 2026-05-01
- DOI
- https://doi.org/10.1002/alz.71455
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Alzheimer's Association
- National Institutes of Health
- National Institute on Aging