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.