Development and Performance Assessment of a Novel Plasma p-Tau181 Assay Reflecting Tau Tangle Pathology in Alzheimer’s Disease

Several blood-based assays for phosphorylated tau (p-tau) have been developed to detect brain tau pathologies in Alzheimer’s disease (AD). However, plasma p-tau measured by currently available assays is influenced by brain amyloid and, therefore, could not accurately reflect brain tau deposits. Here, we devised a novel immunoassay that can quantify N- and C-terminally truncated p-tau fragments (mid-p-tau181) in human plasma. We measured plasma p-tau181 levels in 164 participants who underwent both amyloid and tau positron emission tomography (PET) scans using mid-p-tau181 and conventional p-tau181 assays. The mid-p-tau181 assay displayed stronger correlations with tau PET accumulation than the conventional assay in the AD continuum and accurately distinguished between tau PET-positive and -negative cases. Furthermore, the mid-p-tau181 assay demonstrated a trajectory similar to tau PET alongside cognitive decline. Consequently, our mid-p-tau181 assay could be useful in evaluating the extent of brain tau burden in AD. ### Competing Interest Statement Hitoshi Shimada, Ming-Rong Zhang, and Makoto Higuchi hold patents on compounds related to the present report (JP 5422782/EP 12 884 742.3/CA2894994/HK1208672). ### Clinical Trial UMIN000041383 ### Funding Statement This study was supported in part by AMED under Grant Numbers JP18dm0207018, JP19dm0207072, JP18dk0207026, JP19dk0207049, 21wm0425015h0001, and 20356533; MEXT KAKENHI under Grant Numbers JP16H05324 and JP18K07543; JST under Grant Numbers JPMJCR1652 and JPMJMS2024; and the Kao Research Council for the Study of Healthcare Science, Biogen Idec Inc. and APRINOIA Therapeutics. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Certified Review Board of National Institutes for Quantum Science and Technology gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data supporting this study’s findings are available from the corresponding author on reasonable request. Sharing and reuse of data require the expressed written permission of the authors, as well as clearance from the Institutional Review Boards.