Plasma eMTBR-tau243 and p-tau205 as T2 biomarkers for biological staging and prognosis in Alzheimer’s disease
Abstract
Abstract 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.
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Authors: S.F. Yim, Eun Hye Lee, J Lee, Daeun Shin, Heekyoung Kang, Hee Kyung Park, Seonghyeon Kim, Joel B. Braunstein, Philip B. Verghese, Tim West, Matthew R. Meyer, Theresa A. Day, Henrik Zetterberg, Fernando González‐Ortiz, Nicholas James Ashton, Tobias Bittner, Annunziata Di Domenico, Gwendlyn Kollmorgen, Hyemin Jang, Jihwan Yun, Min Young Chun, Duk Lyul Na, Hee Jin Kim, Yuna Gu, Jun Pyo Kim, Sang Won Seo
Institutions: Yonsei University, Inje University, Inje University Haeundae Paik Hospital, Yonsei University Health System, Sahlgrenska University Hospital, Samsung Medical Center, Indiana University School of Medicine, Indiana University – Purdue University Indianapolis, University of Ulsan, Asan Medical Center, Soonchunhyang University, Soonchunhyang University Hospital Seoul, University of Gothenburg, Sungkyunkwan University, F. Hoffmann-La Roche AG, King's College London, Stavanger University Hospital, Severance Hospital, Kyung Hee University, South London and Maudsley NHS Foundation Trust, Kyung Hee University Dental Hospital, Eli Lilly (United States), Hallym University Chuncheon Sacred Heart Hospital, C2N Diagnostics (United States), Roche Diagnostics International AG (Switzerland)