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.

INTRODUCTION: Alzheimer's disease (AD) pathology is defined by ß-amyloid (Aß) 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, Aß 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 Aß 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 Aß 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.

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

INTRODUCTION: CSF α-synuclein seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body (LB) co-pathology in AD. METHODS: 1637 cross-sectional and 407 longitudinal CSF samples from ADNI were tested with SAA. We examined longitudinal dynamics of Aß, 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-. RESULTS: SAA+ individuals had faster cognitive decline than SAA-, notably in MCI, and presented with earlier symptom onset. SAA+ conversion was associated with CSF Aß42-positivity but did not impact progression of either Aß42 or p-tau181 status. Aß42, p-tau181, and α-syn SAA were all strong predictors of clinical progression, particularly Aß42. In vitro α-syn SAA kinetic parameters were associated with participant demographics, clinical profiles, and cognitive decline. DISCUSSION: These results highlight the interplay between Aß and α-synuclein and their association with disease progression.