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Observational Study
. 2025 Nov 1;82(11):1122-1134.
doi: 10.1001/jamaneurol.2025.3217.

Plasma Phosphorylated Tau 217 to Identify Preclinical Alzheimer Disease

Gemma Salvadó  1   2 , Shorena Janelidze  1 , Divya Bali  1 , Anna Orduña Dolado  1 , Joseph Therriault  3   4 , Wagner S Brum  5   6 , Alexa Pichet Binette  1 , Erik Stomrud  1   7 , Niklas Mattsson-Carlgren  1   7   8 , Sebastian Palmqvist  1   7 , Emma M Coomans  9   10 , Charlotte E Teunissen  11   12 , Wiesje M van der Flier  9   12   13 , Nesrine Rahmouni  3   4 , Tammie L S Benzinger  14   15 , Juan Domingo Gispert  2   16   17   18   19 , Kaj Blennow  20   21   22   23 , Vincent Doré  24   25 , Azadeh Feizpour  26   27   28 , Christopher C Rowe  26   27   28 , Daniel Alcolea  29   30 , Juan Fortea  29   30   31 , Sylvia Villeneuve  32   33 , Sterling C Johnson  34   35 , Pedro Rosa-Neto  3   4   36 , Ronald C Petersen  37 , Clifford R Jack Jr  38 , Suzanne E Schindler  14   15 , Marc Suárez-Calvet  2   18   39 , Rik Ossenkoppele  1   12   40 , Oskar Hansson  1 ; ADNI, ALFA, and PREVENT-AD Study Groups
Collaborators, Affiliations
Observational Study

Plasma Phosphorylated Tau 217 to Identify Preclinical Alzheimer Disease

Gemma Salvadó et al. JAMA Neurol. .

Erratum in

  • Error in Key Points and Methods.
    [No authors listed] [No authors listed] JAMA Neurol. 2025 Nov 17. doi: 10.1001/jamaneurol.2025.4658. Online ahead of print. JAMA Neurol. 2025. PMID: 41247748 No abstract available.

Abstract

Importance: Advances in Alzheimer disease (AD) have shifted research focus to earlier disease stages, necessitating more scalable approaches to identify cognitively unimpaired individuals with amyloid β (Aβ) pathology.

Objective: To assess the utility of plasma phosphorylated tau 217 (p-tau217) for classifying Aβ status in cognitively unimpaired individuals, both as a stand-alone test and in a 2-step approach where positive plasma results were confirmed using a second modality (Aβ positron emission tomography [PET] or cerebrospinal fluid [CSF]).

Design, setting, and participants: This cross-sectional cohort study used data collected between June 2009 and March 2024. We included 2916 cognitively unimpaired participants from 12 international independent observational cohorts in the US, Europe, Australia, and Canada with available plasma p-tau217 levels and CSF or PET Aβ biomarkers. Performance comparisons between mass spectrometry and immunoassay-based p-tau217 measurements were also performed (n = 964).

Exposures: Plasma p-tau217 levels measured by immunoassay.

Main outcome and measures: Aβ status, determined by CSF or Aβ PET biomarkers.

Results: Participants had a mean (SD) age of 66.9 (9.9) years; 971 (33.3%) were Aβ positive by either CSF or PET, 1667 (57.2%) were women, and 1108 (38.1%) carried at least 1 APOE ε4 allele. As a stand-alone test, plasma p-tau217 achieved a positive predictive value (PPV) of 79% (95% CI, 74-84) and an overall accuracy of 81% (95% CI, 80-82). In a 2-step workflow, the PPV and accuracy significantly increased to 91% (95% CI, 86-95). While this approach required screening of 677 individuals with plasma p-tau217 to identify 100 Aβ-positive individuals, compared to 536 participants when using PET alone, it reduced the need for PET testing to 124. Immunoassays demonstrated comparable PPVs to mass spectrometry (80% [95% CI, 74-86] vs 85% [95% CI, 81-90]; P = .12) but significantly lower overall accuracy (82% [95% CI, 79-84]% vs 88 [95% CI, 86-90]; P < .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P < .001).

Conclusions and relevance: The findings highlight the potential of plasma p-tau217 as a stand-alone test-or when used in a sequential 2-step approach alongside PET or CSF testing-as a cost-effective, scalable, and minimally burdensome strategy for identifying preclinical AD. Tailored screening workflows that incorporate p-tau217 can improve efficiency in participant selection for preclinical AD trials and, in the future, help guide access to disease-modifying treatments.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Salvadó reported grants from European Union’s Horizon 2020 Research and Innovation Program under Marie Skłodowska-Curie action, Alzheimer’s Association Research Fellowship, Brightfocus Foundation, Alzheimerfonden, Greta och Johan Kocks, and Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s Disease) during the conduct of the study as well as personal fees from Springer, Adium, Biogen, and GE Healthcare outside the submitted work. Dr Janelidze reported grants from Swedish Alzheimer Foundation outside the submitted work. Dr Therriault reported personal fees from Alzheon and Neurotorium outside the submitted work. Dr Mattsson-Carlgren reported personal fees from Eli Lilly, Merck, and Biogen outside the submitted work. Dr Palmqvist reported research support (paid to institution) from Avid and ki:elements through Alzheimer’s Drug Discovery Foundation. In the past 3 years, he has received consultancy and/or speaker fees from BioArtic, Biogen, Eisai, Eli Lilly, Novo Nordisk, and Roche. Dr Teunissen reported grants from the European Commission, Innovative Medicines Initiatives 3TR, the European UnionJoint Programme–Neurodegenerative Disease Research, European Partnership on Metrology, cofinanced from the European Union’s Horizon Europe Research and Innovation Programme and by the Participating States, Horizon Europe, CANTATE project funded by the Alzheimer Drug Discovery Foundation, Alzheimer Association, Michael J Fox Foundation, Health~Holland, Dutch Research Council, Alzheimer Drug Discovery Foundation, and Selfridges Group Foundation; is a recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW and Health~Holland, Topsector Life Sciences & Health and of TAP-dementia, a ZonMw funded project in the context of the Dutch National Dementia Strategy; has research contracts with Acumen, ADx Neurosciences, AC-Immune, Alamar, Aribio, Axon Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, C2N diagnostics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Merck, Muna, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama, Vaccinex, Vivoryon; serves as editor in chief of Alzheimer Research and Therapy and on editorial boards of Molecular Neurodegeneration, Alzheimer’s & Dementia, Neurology: Neuroimmunology & Neuroinflammation, Medidact Neurologie/Springer, and is a committee member to define guidelines for cognitive disturbances and acute neurology in the Netherlands; and has consultancy or speaker contracts for Aribio, Biogen, Beckman-Coulter, Cognition Therapeutics, Eisai, Eli Lilly, Merck, Novo Nordisk, Novartis, Olink, Roche, Sanofi, and Veravas. Dr van der Flier reported grants from ZonMW, Dutch Research Council, European Union Joint Programme–Neurodegenerative Disease Research, European Union Innovative Health Initiative, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences & Health, stichting Dioraphte, Noaber Foundation, Pieter Houbolt Fonds, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, Philips, Biogen, Novartis-NL, Life-MI, Avid, Roche, Eli Lilly–NL, Fujifilm, Eisai, and Combinostics and is a recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW, Health~Holland, Topsector Life Sciences & Health; TAP-dementia, receiving funding from ZonMw, Avid Radiopharmaceuticals, Roche, and Amprion; Innovative Health Initiative–PROMINENT and Innovative Health Initiative–AD-RIDDLE, which are supported by the Innovative Health Initiative Joint Undertaking, the European Union’s Horizon Europe research and innovation programme and COCIR, European Federation of Pharmaceutical Industries and Associations, EuropaBio, MedTech Europe, and Vaccines Europe, with Davos Alzheimer’s Collaborative, Combinostics Oy, C2N Diagnostics, and neotiv during the conduct of the study (all funding paid to institution); Dr van der Flier also reports speaking at Biogen, Danone, Eisai, WebMD Neurology (Medscape), Novo Nordisk, Springer Healthcare, and the European Brain Council; consulting for Oxford Health Policy Forum, Roche, Biogen, Eisai, Eli Lilly, and Owkin France; participating on advisory boards for Biogen, Roche, and Eli Lilly; serving as a member of the steering committee for the phase 3 EVOKE/EVOKE+ studies (Novo Nordisk), TRONTIER 1 and 2 (Roche), PAVE, and Think Brain Health; serving as a member of the scientific leadership group of InRAD, and associate editor at Brain, the supervisory board at Trimbos Instituut outside the submitted work (any fees paid to institution). Dr Benzinger reported grants from Avid Radiopharmaceuticals during the conduct of the study and consultant or advisory board fees from Eisai, Eli Lilly, and J&J outside the submitted work. Dr Gispert reported grants from GE Healthcare that provided Flutemetamol doses for the ALFA+ study during the conduct of the study; grants from Hoffmann La Roche and personal fees from Life Molecular Imaging and Esteve outside the submitted work; Dr Gispert also received research support from GE HealthCare, Roche Diagnostics, and Hoffmann La Roche and speaking or consulting fees from Roche Diagnostics, Philips Nederlands, Esteve, Biogen, and Life Molecular Imaging; served on the molecular neuroimaging advisory board of Prothena Biosciences; and is founder and co-owner of BetaScreen; Dr Gispert also reports employment at AstraZeneca. Dr Blennow reported having served as a consultant and on advisory boards for AbbVie, AC Immune, ALZPath, AriBio, Beckman-Coulter, BioArctic, Biogen, Eisai, Lilly, Moleac, Neurimmune, Novartis, Ono Pharma, Prothena, Quanterix, Roche Diagnostics, Sanofi, and Siemens Healthineers; has served on data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials, and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai, and Roche Diagnostics; and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the written work. Dr Rowe reported advisory fees from Cerveau Technologies during the conduct of the study and grants from Eisai to assist recruitment in the AHEAD preclinical lecanemab trial outside the submitted work; in addition, Dr Rowe had a patent issued for CapAIBL software (automated analysis of amyloid positron emission tomography). Dr Alcolea reported grants from Instituto de Salud Carlos III during the conduct of the study and personal fees from Fujirebio-Europe, Roche, Nutricia, Krka Farmacéutica, Grifols, Eli Lilly, Zambon, Esteve, and Neuraxpharm outside the submitted work; in addition, Dr Alcolea had a patent licensed to ADx. Dr Fortea reported grants from Fondo de Investigaciones Sanitario, Instituto de Salud Carlos III, the National Institutes of Health, Generalitat de Catalunya Spain, Fundació Tatiana Pérez de Guzmán el Bueno, Alzheimer´s Association, Brightfocus, and Horizon 2020 (European Commission) during the conduct of the study and personal fees from Ionis, AC Immune, Roche, Esteve, Biogen, Adamed, Eisai, Eli Lilly, Zambon, and Perha outside the submitted work; in addition, Dr Fortea had a patent issued for WO2019175379 (A1 markers of synaptopathy in neurodegenerative disease). Dr Johnson reported grants from the National Institutes of Health during the conduct of the study and personal fees from Enigma Biomedical and Eli Lilly outside the submitted work. Dr Rosa-Neto reported funding from Weston Brain Institute for neuroinflammation research, the Canadian Institutes of Health Research for tau propagation research, Fonds de Recherche du Québec–Santé for aging cohort, and the Colin J. Adair Charitable Foundation for student support and advisory board fees from Novo Nordisk, Eisai, and Eli Lilly. Dr Petersen reported grants from the National Institute on Aging and the GHR Foundation during the conduct of the study as well as personal fees from Roche, Genentech, Eli Lilly, Novartis, and Novo Nordisk; other from Eisai; royalties from Oxford University Press; and producing educational materials for UpToDate and Medscape. Dr Schindler reported grants from the National Institute on Aging during the conduct of the study as well as consulting or advisory board fees from Eisai, Novo Nordisk, and Eli Lilly outside the submitted work; Dr Schindler’s institution (Washington University) has an equity interest in C2N Diagnostics; Dr Schindler reports no personal financial interests in C2N. Dr Suárez-Calvet reported nonfinancial support from Avid Radiopharmaceuticals and Eli Lilly (provided in-kind biomarker measurements to the institution); grants (paid to institution) from Roche Diagnostics, lecture or advisory board fees (paid to institution) from Roche Diagnostics, Almirall, Eli Lilly, Novo Nordisk Grifols outside the submitted work; and in-kind support for research (to the institution) from ADx Neurosciences, Alamar Biosciences, ALZpath, Avid Radiopharmaceuticals, Eli Lilly, Fujirebio, Janssen Research & Development, Meso Scale Discovery, and Roche Diagnostics. Dr Ossenkoppele reported research support from Avid Radiopharmaceuticals, Janssen Research & Development, Roche, Quanterix, and Optina Diagnostics; has given lectures in symposia sponsored by GE Healthcare and received speaker fees from Springer; and is an advisory board or steering committee member for Asceneuron, Biogen, and Bristol Myers Squibb; all of the aforementioned has been paid to his institutions. Dr Hansson reported employment at Eli Lilly. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Plasma Phosphorylated Tau 217 (P-tau217) as a Stand-Alone Confirmatory Marker of Amyloid β (Aβ) Positivity
A, A schematic overview of the plasma-only approach is depicted. B-D, Clinical accuracy of plasma p-tau217 is shown for 2 specificity thresholds (95% and 97.5%) across different reference standards: Aβ positivity assessed by either Aβ positron emission tomography (PET) or cerebrospinal fluid (CSF) (B), CSF only (C), and Aβ PET only (D). Dashed lines represent the maximum values achievable by a perfect biomarker. The percentage of positive individuals selected by plasma is shaded in the right column. In the bar plots, individuals who would not be selected out of those who were Aβ positive (ie, false-negative rate) are shown in a lighter color. E-G, Cross-tables display predicted vs reference status for each outcome stratified by specificity thresholds. PPV indicates positive predictive value.
Figure 2.
Figure 2.. Comparison of Clinical Accuracy Between the 2-Step Approach, Plasma Only, and Cerebrospinal Fluid (CSF) or Positron Emission Tomography (PET) Strategies
A, Schematic representation of the 2-step approach. B-C, Statistical results are shown for using CSF (B) or amyloid β (Aβ) PET (C) as the reference standard. Dashed lines indicate the maximum achievable values for a perfect biomarker. The percentage of positive individuals selected by each technique is shaded in the right column. In the bar plots, individuals who would not be selected out of those who were Aβ positive (ie, false-negative rate) are shown in a lighter color. Plasma positivity was determined using a threshold based on 95% specificity across all approaches. D-E, Cross-tables illustrate predicted vs reference status for each outcome, comparing the 3 approaches. P-tau217 indicates phosphorylated tau 217; PPV, positive predictive value.
Figure 3.
Figure 3.. Implications of Different Recruitment Strategies for a Hypothetical Clinical Trial Enrolling 100 Amyloid β (Aβ)-Positive Participants
The figure compares the impact of 5 recruitment strategies: positron emission tomography (PET) only, cerebrospinal fluid (CSF) only, plasma only, a 2-step approach using plasma followed by CSF, and a 2-step approach using plasma followed by PET. Results are presented separately using CSF (A-C) or PET (D-F) as the reference standard for Aβ positivity. The first column (A and D) shows the number of individuals that would need to be initially screened under each approach for achieving 100 Aβ-positive individuals. The second column (B and E) shows the number of CSF or PET confirmatory tests required for each approach. The third column (C and F) shows the number of individuals ultimately included in the trial. Individuals who would be included but were Aβ negative (ie, false positives) are shown in a lighter color. Plasma positivity was determined using a threshold set at 95% specificity across all approaches. P-tau217 indicates phosphorylated tau 217.
Figure 4.
Figure 4.. Comparison of Plasma Only as a Confirmatory Test for Prediction of Amyloid Positivity Using Mass Spectrometry vs Highly Accurate Immunoassay
Clinical accuracy of plasma phosphorylated tau 217 measured by mass spectrometry and immunoassay is compared for assessing amyloid β (Aβ) positivity based on either cerebrospinal fluid (CSF) or positron emission tomography (PET), using thresholds set at 95% specificity in the whole sample. Dashed lines indicate the maximum values achievable by a perfect biomarker. The percentage of positive individuals selected by plasma is shaded in the right column. In the bar plots, individuals who would not be selected out of those who were Aβ positive (ie, false-negative rate) are shown in a lighter color. Mass spectrometry methods were all performed at Washington University or by C2N Diagnostics, independently for each cohort. Immunoassay methods included Eli Lilly and Janssen platforms. PPV indicates positive predictive value. aStatistically significant differences (P < .05) in the specified statistic when comparing immunoassay to mass spectrometry.
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