α-Synuclein Seed Amplifications Assay in a Cohort With Cognitive Impairment: Performance and Interactions With CSF and Plasma Biomarkers.

BACKGROUND AND OBJECTIVES

α-Synuclein seed amplification assays (αSAAs) can improve the diagnosis of synucleinopathies and detect α-synuclein (αSyn) copathology in vivo in clinical practice. We aimed to evaluate the diagnostic performance of αSAA for detecting αSyn in CSF for diagnosing dementia with Lewy bodies (DLB) in a clinical cohort of cognitively impaired individuals. We explored how the coexistence of Alzheimer disease (AD) and αSyn pathology influences biomarker levels and clinical profiles. This study contributes to the understanding of αSAA diagnostic performance for DLB and for detecting αSyn copathology in AD in a real-world memory clinic cohort, using both clinical and biomarker-based classifications.

METHODS

This was a retrospective, single-center, cross-sectional observational cohort study of cognitively impaired individuals who attended a tertiary memory clinic in Spain between 2009 and 2024. Participants had neurodegenerative and non-neurodegenerative cognitive decline. αSAA was performed on CSF samples collected at first evaluation. The diagnostic performance of the assay for DLB and associations between AD/αSyn copathology, clinical features, and fluid biomarkers (phosphorylated-tau217 [p-tau217], glial fibrillary acidic protein, neurofilament light chain [NfL]) were analyzed in AD and DLB participants. Diagnostic performance of the test was assessed using standard contingency tables and interactions between biomarkers and clinical features with age, sex, and APOE-adjusted analysis of covariance.

RESULTS

A total of 640 participants were included (mean age 67.8 years, 48% female) with clinical diagnoses of AD (n = 337), DLB (n = 92), frontotemporal lobar degeneration (n = 79), non-neurodegenerative cognitive impairment (n = 100), and cognitively unimpaired controls (n = 32). αSAA exhibited a 95.7% sensitivity (95% CI 91.6%-99.8%), 93.2% specificity (95% CI 90.4%-96.0%), and a 93.6% overall diagnostic accuracy for DLB. Among patients with AD, 9.5% were αSAA positive; these individuals more often had core DLB features at presentation, higher APOE ε4 frequency, and elevated plasma p-tau217. Fifty percent of DLB patients showed AD copathology, associated with lower Mini-Mental State Examination scores, higher APOE ε4 prevalence, and higher CSF and plasma NfL. αSAA+ AD subjects had significantly higher p-tau217 and CSF p-tau181 than DLB AD+ patients.

DISCUSSION

αSAA demonstrated high diagnostic accuracy for DLB, supporting its clinical utility. AD-DLB copathology is associated with distinct cognitive and biomarker profiles, with varying levels of pathology shaping the clinical phenotype (AD- or DLB-predominant). These findings highlight the need for tailored diagnostic and therapeutic approaches.