Plasma eMTBR-tau243 and p-tau205 as T2 biomarkers for biological staging and prognosis in Alzheimer’s disease

Plasma biomarkers that reflect distinct stages of Alzheimer’s disease (AD) could enable scalable biological staging. We evaluated phosphorylated tau (p-tau) species across multiple analytical platforms and the endogenously cleaved microtubule-binding region containing residue 243 (eMTBR-tau243) using a dedicated LC-MS/MS platform in a well-characterized cohort with amyloid PET and a subset with tau PET. While T1 biomarkers increased during preclinical stages, eMTBR-tau243 and p-tau205 increased later, consistent with fibrillar tau aggregation. eMTBR-tau243 showed the strongest and stage-dependent associations with regional tau PET and cognition, outperforming T1 biomarkers in predicting cross-sectional and longitudinal cognition. A plasma-based tau staging system integrating p-tau217 and eMTBR-tau243 closely aligned with PET-based tau staging and predicted longitudinal cognitive trajectories. These findings support plasma eMTBR-tau243 as a prototypical T2 biomarker and highlight the potential of plasma-based tau staging for prognosis and therapeutic decision-making in AD.