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

In 615 ADNI participants, CSF alphaSyn SAA positivity (117; 19.0%) is linked to a steeper amyloid–meta-temporal tau association cross-sectionally (interaction beta 0.258, p=0.032).

• Why it matters: The study addresses whether alphaSyn co-pathology modifies the human amyloid–tau–cognition cascade, which is unclear despite synergy in animal models.
• What they did: Using linear models on regional flortaucipir tau PET and amyloid PET plus domain-specific cognition within 1 year of tau PET, and mixed-effects models over a median 3.5 years (n=341 tau PET; n=516 cognition).
• The result: The amyloid–tau interaction did not survive false discovery rate correction (q=0.072) and showed no longitudinal alphaSyn×amyloid×time effect (meta-temporal beta -0.012, p=0.513); alphaSyn positivity related to lower executive function at mean tau (q=0.032) and a less steep tau-related executive decline longitudinally (q=0.042).