Distinct molecular trajectories precede amyloid-β and tau pathology in Alzheimer’s disease

Alzheimer’s disease (AD) progresses over a prolonged preclinical phase marked by early amyloid-β pathology (Aβ), followed by tau spread and neurodegeneration. However, limited understanding of longitudinal, stage-specific molecular processes constrains therapeutic timing and patient stratification. Here, we reconstructed molecular trajectories across the AD continuum by integrating longitudinal cerebrospinal fluid (CSF) proteomics with Aβ and tau biomarkers from two independent cohorts. We identified distinct trajectories emerging prior to Aβ and tau conversion. Preclinical Aβ-dominated transitions were characterized by immune- and lipid-associated programs, whereas tau-dominated transitions at the mild cognitive impairment stage were linked to synaptic, proteostatic, and autophagy-related signatures. These stage-specific trajectories predicted biomarker conversion, including from the preclinical, pre-Aβ stage. Longitudinal voxelwise analyses further revealed spatially distinct cortical Aβ and tau patterns corresponding to inflammatory and proteostatic-synaptic signatures. Together, these findings define temporally ordered molecular pathways underlying AD progression and inform stage-specific therapeutic strategies.