A cross‐sectional study of α‐synuclein seed amplification assay in Alzheimer's disease neuroimaging initiative: Prevalence and associations with Alzheimer's disease biomarkers and cognitive function

Abstract INTRODUCTION Alzheimer's disease (AD) pathology is defined by β‐amyloid (Aβ) plaques and neurofibrillary tau, but Lewy bodies (LBs; 𝛼‐synuclein aggregates) are a common co‐pathology for which effective biomarkers are needed. METHODS A validated α‐synuclein Seed Amplification Assay (SAA) was used on recent cerebrospinal fluid (CSF) samples from 1638 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 78 with LB‐pathology confirmation at autopsy. We compared SAA outcomes with neuropathology, Aβ and tau biomarkers, risk‐factors, genetics, and cognitive trajectories. RESULTS SAA showed 79% sensitivity and 97% specificity for LB pathology, with superior performance in identifying neocortical (100%) compared to limbic (57%) and amygdala‐predominant (60%) LB‐pathology. SAA+ rate was 22%, increasing with disease stage and age. Higher Aβ burden but lower CSF p‐tau181 associated with higher SAA+ rates, especially in dementia. SAA+ affected cognitive impairment in MCI and Early‐AD who were already AD biomarker positive. DISCUSSION SAA is a sensitive, specific marker for LB‐pathology. Its increase in prevalence with age and AD stages, and its association with AD biomarkers, highlights the clinical importance of α‐synuclein co‐pathology in understanding AD's nature and progression. Highlights SAA shows 79% sensitivity, 97% specificity for LB‐pathology detection in AD. SAA positivity prevalence increases with disease stage and age. Higher Aβ burden, lower CSF p‐tau181 linked with higher SAA+ rates in dementia. SAA+ impacts cognitive impairment in early disease stages. Study underpins need for wider LB‐pathology screening in AD treatment.