Combination of CSF α-synuclein seed amplification assay and amyloid-β42 predicts cognitive decline in Parkinson's disease

Cognitive impairment is a disabling non-motor feature of Parkinson's disease (PD). Cerebrospinal fluid (CSF) α-synuclein seed amplification assay (SAA) reflects Lewy body pathology, while reduced CSF amyloid-β42 (Aβ42) indicates Alzheimer's type co-pathology in PD. This study examined whether combined CSF α-synuclein SAA and Aβ42 status improves prediction of cognitive decline and dementia risk in PD. A total of 692 participants (145 controls and 547 individuals with PD) from the Parkinson's Progression Markers Initiative with available CSF α-synuclein SAA and Aβ42 measurements were included. Participants were classified into four biomarker-defined groups based on α-synuclein/amyloid (S/A) status: S − A− ( n = 140), S − A+ ( n = 67), S + A− ( n = 307), and S + A+ ( n = 178). At baseline, α-synuclein SAA positivity was highly prevalent in PD (87.2%). APOE ε4 carrier frequency differed significantly across groups ( p < 0.001), with the highest prevalence in S − A+ (50.8%) and S + A+ (33.7%). The S + A+ group exhibited the lowest baseline cognitive scores, with intermediate deficits in S + A−. Longitudinally, S + A+ participants showed the steepest cognitive decline ( p < 0.001), whereas the S + A− and S − A+ groups demonstrated more modest but significant declines. In multivariable Cox regression, each one-category increase in S/A status was associated with a higher hazard of dementia (HR = 2.72, 95% CI 1.80–4.08, p < 0.001). Combined CSF α-synuclein and Aβ42 stratification identifies subgroups at high risk for accelerated cognitive decline and dementia, offering a potential strategy to improve prognostic precision and clinical trial design in PD. • Combined CSF α-synuclein and Aβ42 status improves prediction of cognitive decline. • Dual-positive biomarker status identifies PD patients at highest dementia risk. • CSF biomarker profiles define subgroups with distinct long-term cognitive trajectories.