Alpha‐synuclein co‐pathology in a real‐world early Alzheimer's disease cohort

BACKGROUND: Most Alzheimer's disease (AD) cases show mixed pathology, with α-synuclein (αSyn) aggregates present in a substantial proportion. The cerebrospinal fluid (CSF) α-synuclein seed amplification assay (αS-SAA) enables in vivo detection of pathogenic αSyn aggregates, but its clinical significance remains unclear. METHODS: We prospectively evaluated 108 individuals with mild cognitive impairment or mild dementia due to suspected AD undergoing lumbar puncture for anti-amyloid therapy (ATT) eligibility. CSF AD biomarkers and αS-SAA were analyzed alongside cognitive, olfactory, and rapid eye movement sleep behavior disorder (RBD) assessments. RESULTS: Of 65 participants with biomarker-confirmed AD, 21 (32.3%) were αS-SAA positive. Positivity was linked to older age at testing and self-reported olfactory impairment (P = 0.004), but not other demographic or cognitive features. Within the αS-SAA-positive group, RBD presence correlated with faster seeding kinetics. CONCLUSIONS: αS-SAA positivity is common in early AD and associated with olfactory dysfunction. Longitudinal follow-up is required to test if assay status predicts response to ATTs.