Effects of α-synuclein pathology in normal aging and Alzheimer’s disease

Objective α-synuclein is the hallmark pathology of Parkinson’s disease and dementia with Lewy bodies, described together as Lewy body disease (LBD). α-synuclein is also commonly observed in the context of Alzheimer’s disease (AD). Here we investigate the frequency of α-synuclein biomarker positivity in clinically unimpaired (CU) individuals and an AD research cohort, as well as associations with demographics, AD biomarkers, cognitive performance, and clinical outcomes. Methods We assessed α-synuclein status (α-syn+/-) in 270 CU and 56 clinically diagnosed AD participants (29 mild cognitive impairment and 27 dementia) using a cerebrospinal fluid seed amplification assay (α-syn SAA). Eighty-five LBD spectrum participants were included for comparison. AD biomarker levels were measured with cerebrospinal fluid β-amyloid42/40 and p-tau181. Participants received cognitive testing, the Neuropsychiatric Inventory Questionnaire and the Movement Disorders Society Unified Parkinson’s Disease Rating Scale. Results α-syn was detected in 9% of CU, 14% of AD mild cognitive impairment, and 19% of AD dementia participants, whereas 81% of individuals with LBD spectrum clinical diagnoses were α-syn+. α-syn+ CU were older, performed worse on tests of executive function and working memory, and reported more LBD-related non-motor symptoms relative to α-syn-CU. α-syn status in CU was not significantly associated with β-amyloid or tau, memory performance, motor symptoms, or neuropsychiatric symptoms. Conclusions Using the CSF SAA biomarker, α-syn positivity independently predicts subtle cognitive changes and early clinical symptoms in aging. These cross-sectional findings represent an important addition to the limited but growing literature characterizing the frequency and effects of α-syn positivity in clinically healthy older adults and individuals with AD.