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

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

doi:10.1002/alz.71455

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

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

Authors

Joseph R Winer¹, Melanie J Plastini¹, America Romero¹, Hillary Vossler¹, Isha Sai¹, Divya Channappa¹, Carla Abdelnour¹, Marian Shahid-Besanti¹, Edward N Wilson^{1

2

3}, Hamilton Se-Hwee Oh^{4

5

6

7}, Christina B Young^{1

8

9}, Alexandra Trelle¹, Maya Yutsis¹, Sharon J Sha^{1

2}, Veronica Ramirez¹, Ryan Taylor¹, Kyan Younes¹, Tony Wyss-Coray^{1

2

3}, Michael D Greicius¹, Victor W Henderson^{1

2

10}, Anthony D Wagner^{2

11}, Kathleen L Poston^{1

2}, Elizabeth C Mormino^{1

2

12}

Affiliations

¹ Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, California, USA.
² Wu Tsai Neurosciences Institute, Stanford University, Stanford, California, USA.
³ The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, California, USA.
⁴ Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁵ Brain and Body Research Center of the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁶ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁷ Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁸ Department of Radiology, University of California Davis, Sacramento, California, USA.
⁹ Department of Neurology, University of California Davis, Sacramento, California, USA.
¹⁰ Department of Epidemiology and Population Health, Stanford University, Stanford, California, USA.
¹¹ Department of Psychology, Stanford University, Stanford, California, USA.
¹² Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California, USA.

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.

Keywords: Lewy body; SAA; co‐pathology; synaptic dysfunction.

MeSH terms

Aged
Aged, 80 and over
Aging* / cerebrospinal fluid
Aging* / pathology
Alzheimer Disease* / cerebrospinal fluid
Alzheimer Disease* / pathology
Biomarkers / cerebrospinal fluid
Female
Humans
Lewy Body Disease* / cerebrospinal fluid
Lewy Body Disease* / pathology
Male
Middle Aged
Neuropsychological Tests
Synapses* / pathology
alpha-Synuclein* / cerebrospinal fluid

Substances

alpha-Synuclein
Biomarkers

Abstract

MeSH terms

Substances

Grants and funding