Association of CSF α-Synuclein Seed Amplification Assay Positivity with Disease Progression and Cognitive Decline: A Longitudinal Alzheimer’s Disease Neuroimaging Initiative Study

Abstract

INTRODUCTIONCSF α-synuclein seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body (LB) co-pathology in AD.METHODS1637 cross-sectional and 407 longitudinal CSF samples from ADNI were tested with SAA. We examined longitudinal dynamics of Aβ, α-synuclein seeds, and p-tau181, along with global and domain-specific cognition in stable SAA+, stable SAA−, and those who converted to SAA+ from SAA−.RESULTSSAA+ individuals had faster cognitive decline than SAA−, notably in MCI, and presented with earlier symptom onset. SAA+ conversion was associated with CSF Aβ42-positivity but did not impact progression of either Aβ42 or p-tau181 status. Aβ42, p-tau181, and α-syn SAA were all strong predictors of clinical progression, particularly Aβ42. In vitro α-syn SAA kinetic parameters were associated with participant demographics, clinical profiles, and cognitive decline.DISCUSSIONThese results highlight the interplay between Aβ and α-synuclein and their association with disease progression.