Head-to-head comparisons of high-performance plasma phospho-tau epitopes for the detection of Alzheimer's disease

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Project Summary/Abstract Recent studies suggest that plasma assays for phosphorylated tau protein at threonine 231 (p-tau231), threonine 181 (p-tau181), and threonine 217 (p-tau217) are highly associated with both brain amyloid-beta (Ab) and tau pathologies and identify the spectrum of Alzheimer’s disease (AD) with high accuracy. These studies suggest that these simple blood tests for tau phosphorylation offer an unprecedented advance for the diagnosis of AD, bypassing the need for additional biomarkers, including Ab. Plasma p-tau biomarkers have the potential to be incorporated in clinical practice as a rapid screening test to confirm or rule out AD and to guide management of patients with cognitive symptoms. Furthermore, this technology has immediate applications for diagnosis and recruitment in clinical trials and may serve as a tool for monitoring the effects of drug candidates targeting tau pathology. However, preliminary evidence suggests that the different plasma p-tau epitopes may differ widely in sensitivity and specificity to detect AD, depending on the disease's stage at which they are quantified. Thus, a well-powered study measuring p-tau231, p-tau181, and p-tau217 epitopes in the same subjects’ plasma samples across the AD spectrum has the potential to elucidate the advantages and limitations of using each of the plasma p-tau epitopes. This study can also clarify whether the quantification of more than one plasma p-tau epitope can provide complementary information compared to the quantification of a single assay. Understanding the inherent characteristics of each plasma p-tau epitope to detect the AD continuum can be crucial in interpreting conflicting results from studies using the different epitopes that will likely emerge in the coming years. Here, we propose a non-randomized observational biomarker study measuring p-tau231, p-tau181, and p-tau217, Ab, neurofilament light chain, and total tau in stored plasma samples from 1,400 individuals across the AD spectrum, characterized with positron emission tomography (PET) tau and Ab scans, enrolled in well-established cohorts of aging and AD. All individuals will be assessed at baseline, 1-year, and 2-year follow-up visits. In this study, we aim (1) to compare the performance of plasma p-tau epitopes to identify early and late depositions of Ab and tau proteins measured by PET. (2) To compare the performance of plasma p-tau epitopes for the diagnosis of the AD spectrum. (3) To compare the performance of baseline plasma p-tau epitopes concentrations to investigate longitudinal cognitive deterioration. (4) To compare the performance of longitudinal changes in plasma biomarkers for use in clinical trials and their associations with longitudinal changes in PET biomarkers. The results generated in our study will have an impact on the design of several future biomarker programs, shedding light on the performance of the plasma p-tau231, p-tau181, and p-tau217 epitopes for numerous applications in research, clinical trials, and clinical practice.