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. 2024 Mar 1;81(3):255-263.
doi: 10.1001/jamaneurol.2023.5319.

Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology

Nicholas J Ashton  1   2   3   4 , Wagner S Brum  1   5 , Guglielmo Di Molfetta  1 , Andrea L Benedet  1 , Burak Arslan  1 , Erin Jonaitis  6   7   8 , Rebecca E Langhough  6   7   8 , Karly Cody  7 , Rachael Wilson  7   8 , Cynthia M Carlsson  6   7   8   9 , Eugeen Vanmechelen  10 , Laia Montoliu-Gaya  1 , Juan Lantero-Rodriguez  1 , Nesrine Rahmouni  11   12 , Cecile Tissot  11   12 , Jenna Stevenson  11   12 , Stijn Servaes  11   12 , Joseph Therriault  11   12 , Tharick Pascoal  13   14 , Alberto Lleó  15   16 , Daniel Alcolea  15   16 , Juan Fortea  15   16 , Pedro Rosa-Neto  11   12 , Sterling Johnson  6   7 , Andreas Jeromin  17 , Kaj Blennow  1   18 , Henrik Zetterberg  1   7   18   19   20   21
Affiliations

Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology

Nicholas J Ashton et al. JAMA Neurol. .

Abstract

Importance: Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of p-tau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests.

Objective: To determine the utility of a novel and commercially available immunoassay for plasma p-tau217 to detect AD pathology and evaluate reference ranges for abnormal amyloid β (Aβ) and longitudinal change across 3 selected cohorts.

Design, setting, and participants: This cohort study examined data from 3 single-center observational cohorts: cross-sectional and longitudinal data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (visits October 2017-August 2021) and Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort (visits February 2007-November 2020) and cross-sectional data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort (baseline visits March 2009-November 2021). Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023.

Exposures: Magnetic resonance imaging, Aβ positron emission tomography (PET), tau PET, cerebrospinal fluid (CSF) biomarkers (Aβ42/40 and p-tau immunoassays), and plasma p-tau217 (ALZpath pTau217 assay).

Main outcomes and measures: Accuracy of plasma p-tau217 in detecting abnormal amyloid and tau pathology, longitudinal p-tau217 change according to baseline pathology status.

Results: The study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] and 282 males [35.9%]). High accuracy was observed in identifying elevated Aβ (area under the curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95% CI, 0.84-0.99) across all cohorts. These accuracies were comparable with CSF biomarkers in determining abnormal PET signal. The detection of abnormal Aβ pathology using a 3-range reference yielded reproducible results and reduced confirmatory testing by approximately 80%. Longitudinally, plasma p-tau217 values showed an annual increase only in Aβ-positive individuals, with the highest increase observed in those with tau positivity.

Conclusions and relevance: This study found that a commercially available plasma p-tau217 immunoassay accurately identified biological AD, comparable with results using CSF biomarkers, with reproducible cut-offs across cohorts. It detected longitudinal changes, including at the preclinical stage.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Jonaitis reported grants from National Institutes of Health and tau tracer from Cerveau during the conduct of the study. Dr Langhough reported grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Cody reported grants from NIH during the conduct of the study. Dr Wilson reported grants from University of Wisconsin–Madison during the conduct of the study. Dr Carlsson reported grants from NIH during the conduct of the study. Dr Lleó reported personal fees from Fujirebio-Europe, Roche, Biogen, Lilly, and Nutricia outside the submitted work and having had a patent for markers of synaptopathy in neurodegenerative disease licensed to ADx. Dr Alcolea reported grants from Fondo de Investigaciones Sanitario, Carlos III Health Institute, and Departament de Salut de la Generalitat de Catalunya during the conduct of the study; advisory board services and/or speaker honoraria from Fujirebio-Europe, Roche, Nutricia, Krka Farmacéutica, Grifols, Lilly, Zambon, Esteve, and Neuraxpharm outside the submitted work; and having had a patent for EPI8382175.0 licensed to ADx. Dr Fortea reported grants from Fondo de Investigaciones Sanitario (FIS), Instituto de Salud Carlos III, NIH, and Horizon 2020 (European Commission) during the conduct of the study; personal fees from Roche, Novo Nordisk, Esteve, Biogen, Laboratorios Carnot, LMI, AC Immune, Alzheon, Lundbeck, and Lilly outside the submitted work; and having had a patent issued for WO2019175379 A1, “Markers of synaptopathy in neurodegenerative disease,” with royalties paid. Dr Rosa-Neto reported funding from the Weston Brain Institute, Canadian Institutes of Health Research (MOP-11-51-31, FRN, 152985); salary award from the Fonds de Recherche du Québec–Santé and Colin J. Adair Charitable Foundation; serving on the advisory board for Novo Nordisk, Eisai, and Eli Lilly; and serving as a consultant for Eisai and Cerveau Radiopharmaceuticals. Dr Johnson reported grants from NIH and advisory board fees from ALZpath during the conduct of the study, grants from Cerveau Technologies paid to his institution outside of the submitted work, and advisory board fees from Roche Diagnostics and Prothena outside the submitted work. Dr Jeromin reported equity from ALZpath and having had a patent pending for ALZpath. Dr Blennow reported having served as a consultant and at advisory boards for Acumen, ALZpath, BioArctic, Biogen, Eisai, Lilly, Moleac, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; having served at data monitoring committees for Julius Clinical and Novartis; having given lectures, produced educational materials, and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai, and Roche Diagnostics; and being a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Dr Zetterberg reported advisory board fees from AbbVie, Acumen, Alector, Alzinova, ALZpath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave Scientific; sponsored lecture fees from Cellectricon, Fujirebio, Alzecure, Biogen, and Roche; and being a co-founder and stockholder for Brain Biomarker Solutions in Gothenburg AB outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Plasma Phosphorylated Tau 217 (p-Tau217) Levels According to Amyloid β (A) and Tau (T) Profiles
Boxplots show the distribution of p-tau217 concentrations by AT profile for the Wisconsin Registry for Alzheimer’s Prevention (WRAP), Translational Biomarkers in Aging and Dementia (TRIAD), and Sant Pau Initiative on Neurodegeneration (SPIN) cohorts. For WRAP and TRIAD, Aβ and tau were indexed by positron emission tomography. In SPIN, A was indexed by cerebrospinal fluid (CSF) Aβ42/40 and T by CSF p-tau181. All comparison P values obtained from pairwise contrasts from linear models adjusted for age and sex were less than .001, whereas in the SPIN cohort, 2 comparisons showed P < .05. The horizontal line inside each box indicates the median, the outer bounds of boxes represent lower and upper quartiles, and whiskers extend to the 5th and 95th IQRs; circles indicate observed data points. aP = .001. bP < .001. cA+T− vs A+T+: P = .03. dA−T− vs A+T−: P = .02.
Figure 2.
Figure 2.. Accuracy of the Phosphorylated Tau 217 (p-Tau217) Immunoassay in Detecting Amyloid β (Aβ) Positivity and Tau (T) Positivity and Discriminating A+T− From A+T+ Individuals
Receiver operating characteristics (ROC) curves for p-tau217 in detecting Aβ positivity and tau positivity and to differentiating Aβ-positive and tau-positive individuals (A+T+) from Aβ-positive and tau-negative (A+T−). For each ROC curve, the area under the curve is reported alongside 95% CI. For WRAP and TRIAD, Aβ and tau were indexed by positron emission tomography. In SPIN, A was indexed by cerebrospinal fluid (CSF) Aβ42/40 and T by CSF p-tau181.
Figure 3.
Figure 3.. Longitudinal Trajectories of Plasma Phosphorylated Tau 217 (p-Tau217) Values According to Amyloid β (A) and Tau (T) Status by Positron Emission Tomography (PET)
Trajectory plots indicate the mean longitudinal trajectories (solid line) of plasma p-tau217 and associated 95% CIs (shading), estimated with linear mixed-effects models. Trajectories are stratified based on PET-defined amyloid and tau groups (A−T−, A+T−, A+T+), modeled with an interaction term between AT status and time. Models included random slopes and intercepts for each participant and were adjusted for years of education, sex, and cognitive status at first visit. P values represent post hoc pairwise comparing the slopes for group × time interactions. aP < .001.
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