Alpha-synuclein co-pathology amplifies amyloid-driven tau accumulation across Braak stages without modifying tau-cognition associations

INTRODUCTIONAlpha-synuclein (Syn) is the most common co-pathology in Alzheimers disease (AD), yet its role within the amyloid-tau-neurodegeneration (ATN) cascade is unknown. METHODSWe analyzed 636 ADNI participants with CSF Syn seed amplification assay, amyloid PET, regional tau PET (Braak I-VI), structural MRI, and cognitive composites. Interaction models tested whether Syn modifies the amyloid-tau and tau-cognition associations. RESULTSSyn positivity (19.0%) amplified the amyloid-tau association across all Braak stages (meta-temporal interaction {beta} = 0.258, 95% CI 0.104-0.411, p = 0.001), with strongest effects in Braak III-IV. Syn did not modify tau-cognition associations in any domain (all interaction p > 0.18). DISCUSSIONSyn co-pathology selectively amplifies amyloid-driven tau propagation without modifying downstream tau-cognition relationships, identifying a node-specific effect within the ATN cascade with implications for patient stratification. Research in ContextO_ST_ABSSystematic reviewC_ST_ABSWe searched PubMed for studies combining -synuclein seed amplification assays with amyloid and tau PET in Alzheimers disease. One recent study (Franzmeier et al., 2025) demonstrated that -synuclein co-pathology accelerates amyloid-driven tau accumulation. No study has examined whether -synuclein modifies the downstream tau-cognition relationship or assessed regional tau specificity across all Braak stages. InterpretationIn 636 ADNI participants, -synuclein co-pathology amplified the amyloid-tau association across all Braak stages but did not modify tau-cognition relationships. This dissociation identifies -synuclein as a node-specific modifier of the ATN cascade, acting at the amyloid-to-tau transition. Future directionsLongitudinal studies with serial tau PET and -synuclein SAA are needed to establish temporality. Clinical trials should evaluate whether -synuclein stratification improves prediction of anti-amyloid treatment response.