Background: Endogenously cleaved microtubule-binding region tau containing residue 243(eMTBR‑tau243), identified by immunoprecipitation-mass spectrometry (IP‑MS), has been shown to reflect advanced neurofibrillary pathology in Alzheimer’s disease. However, the lack of scalable andautomated immunoassays has limited the clinical translation, and the utility of plasma eMTBR-tau243 for estimating tau PET-based Braak staging using immunoassay platforms remains unclear. In this study, we investigated whether novel automated immunoassays for plasma eMTBR‑tau243 can be used to estimate tau PET-based Braak staging.

Methods: Plasma samples were obtained from 129 participants of the Tokyo Metropolitan Institute for Geriatrics and Gerontology (TMIG) biobank, who had tau PET data using [¹⁸F]MK‑6240. Plasma eMTBR‑tau243 concentrations were quantified using the Automated Immunoassay System HISCL^TM‑5000. PET-based Braak stages were assigned according to established criteria. Associations between plasma eMTBR‑tau243 concentrations and Braak stages were assessed, and receiver operatingcharacteristic (ROC) analyses were performed to evaluate the ability to discriminate tau PET-basedBraak stages.

Results: In the total cohort of 129 participants, plasma eMTBR‑tau243 concentrations increased with advancing tau PET-defined Braak stage. Of these participants, 112 were classified as Braak stage <V and17 as Braak stage ≥V by tau PET. Plasma eMTBR‑tau243 showed high discriminative performance for distinguishing participants with Braak stage ≥V from those with Braak stage <V, achieving an areaunder the receiver operating characteristic curve (AUC) greater than 0.9.

Conclusion: Using an automated immunoassay platform, we demonstrate that plasma eMTBR‑tau243 is associated with tau PET-based Braak staging. These findings support the feasibility of translating mass spectrometry-based discoveries into scalable immunoassays suitable for large-scale clinical and research applications, and highlight the potential utility of plasma tau biomarkers for biological staging in Alzheimer’s disease.