Tau Propagation Causality Test — Does Tau Spread Drive Neurodegeneration or Is It a Bystander?

SUMMARY

# Tau Propagation Causality Test — Does Tau Spread Drive Neurodegeneration or Is It a Bystander? ## Background and Rationale Tau protein aggregation and spread is a hallmark of Alzheimer's disease and other tauopathies, but the causal relationship between tau propagation and neurodegeneration remains unclear. This fundamental knowledge gap has profound therapeutic implications: if tau spread directly causes neurodegeneration, anti-tau therapies could be disease-modifying; if tau is merely a byst

METHODOLOGY NOTES

Phase 1 (Months 0-3): Recruit 150 participants across cognitive spectrum: 50 cognitively normal elderly, 50 mild cognitive impairment, 50 mild AD dementia. Baseline assessments include tau-PET ([18F]MK-6240), amyloid-PET ([18F]florbetapir), structural/functional MRI, lumbar puncture for CSF tau, phospho-tau181, neurofilament light chain, and comprehensive neuropsychological testing. Phase 2 (Months 6, 12, 18, 24): Longitudinal follow-up visits with tau-PET, MRI, CSF sampling, and cognitive testing at each timepoint. Phase 3 (Months 24-30): Advanced imaging analysis using standardized uptake value ratios for tau-PET, cortical thickness measurements, network connectivity analysis, and voxel-wise statistical mapping. Phase 4 (Months 30-36): Statistical modeling using linear mixed-effects models to examine temporal relationships between tau accumulation rates, spread patterns, and neurodegeneration markers. Cross-lagged panel analysis will assess directional relationships. Mediation analys