Alpha-Synuclein Co-Pathology and Amyloid-Tau Coupling in Alzheimer's Disease: Cross-Sectional and Longitudinal Analyses Across Braak Stage Regions

Abstract

**Background:** Misfolded alpha-synuclein (alphaSyn), a common co-pathology in Alzheimer's disease, acts synergistically with amyloid and tau in animal models, but its role in the human amyloid-tau-cognition cascade is unclear. We examined whether alphaSyn modifies the amyloid-tau and tau-cognition associations, cross-sectionally and over time. **Methods:** We analyzed 615 participants from the Alzheimer's Disease Neuroimaging Initiative with a cerebrospinal fluid alphaSyn seed amplification assay (SAA), flortaucipir tau positron emission tomography (PET) in Braak stage regions, and amyloid PET and domain-specific cognitive composites within 1 year of tau PET. Linear models with heteroscedasticity-consistent standard errors tested alphaSyn x amyloid interactions on regional tau and alphaSyn x tau interactions on cognition; mixed-effects models tested the same interactions on repeated tau PET (n = 341) and cognitive testing (n = 516). **Results:** alphaSyn positivity was present in 117 participants (19.0%). Cross-sectionally, the amyloid-tau association was steeper in alphaSyn SAA+ participants for meta-temporal tau (interaction beta 0.258, 95% CI 0.023 to 0.493; p = 0.032) and Braak I-IV (p <= 0.048); no interaction survived false discovery rate correction (q = 0.072), and clinical-stage adjustment attenuated it (beta 0.114; p = 0.333). Over a median of 3.5 years (n = 341; 68 alphaSyn-positive), no alphaSyn x amyloid x time interaction was detected (meta-temporal beta -0.012, 95% CI -0.046 to 0.023; p = 0.513). No cross-sectional alphaSyn x tau interaction on cognition was detected; at mean tau, alphaSyn positivity was associated with lower executive function (q = 0.032). Longitudinally, tau-related executive decline was less steep in alphaSyn-positive participants (q = 0.042). **Conclusions:** The alphaSyn-associated amyloid-tau interaction was modest, did not withstand multiple-testing correction, and had no detected longitudinal counterpart. alphaSyn positivity was associated with poorer executive function at mean tau; the unexpected longitudinal executive interaction needs replication. These findings do not establish alphaSyn status as a marker for tau-progression enrichment in trials.