Plasma proteomics reveals stage-dependent biological remodelling in Alzheimer's disease
Abstract
Plasma biomarkers of amyloid-associated tau phosphorylation (T1) and established tau proteinopathy (T2) can approximate Alzheimer's disease stage, but whether plasma-defined stages correspond to broader biological states is unknown. In 1,035 participants from a multicentre Korean cohort, we used a 220-plex immunoassay platform to compare T1/T2 biomarkers against amyloid and tau positron emission tomography anchors and construct a five-stage framework. Brain-derived phosphorylated tau 217 and endogenously cleaved microtubule-binding-region tau formed the parsimonious backbone. Baseline stage ordered Clinical Dementia Rating-Sum of Boxes trajectories, and forward within-person stage movement was associated with faster clinical worsening. Among 197 non-tau proteins, 34 were stage-associated; the T1-positive transition showed the broadest proteomic shift, with more selective remodelling later. In serial samples, 15 proteins changed longitudinally, with 13 recapitulating the cross-sectional stage pattern. Thus, plasma-defined disease position mapped onto distinct, partly dynamic biological states beyond the defining T1/T2 biomarkers.