Evaluating the Interaction of Alzheimer Biomarker Burden and α-Synuclein Status on Cognitive Trajectories in Parkinson Disease: Methodological Challenges and Power Estimates

Background: Alzheimer disease (AD) and α-synuclein copathology frequently co-occur in Parkinson disease (PD), but whether their interaction accelerates longitudinal cognitive decline is unknown. Objective: To investigate whether the cross-sectional interaction between AD biomarker burden (CSF pTau181/Aβ42 ratio) and α-synuclein seed amplification assay (SAA) status translates to accelerated cognitive decline, and to estimate sample sizes for future co-pathology studies. Methods: We studied 246 dementia-free PD participants from the Parkinson Precision Medicine Initiative, including genetically enriched subgroups, across seven cognitive domains over 12.9 years. Longitudinal trajectories were modeled using inverse probability of continuation weighted generalized estimating equations with Firth penalization, confirmed by linear mixed-effects and Bayesian joint models. Results: A cross-sectional AD×SAA visuospatial synergy was replicated ( P =0.022), but no longitudinal interaction survived false discovery rate correction (all q ≥0.180). However, a nominally significant AD×SAA interaction on verbal memory was detected by subject-specific models ( P =0.018 to 0.026). Power simulations indicated that 400 to 600 participants under enriched designs, or over 1000 under naturalistic conditions, are required for 80% power. Conclusions: Cross-sectional biomarker synergies may not predict accelerated longitudinal decline in early PD. Future copathology studies require strict attrition correction, quantitative α-synuclein measures, and targeted enrichment strategies.