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What is the discriminative accuracy of plasma phospho-tau217 (P-tau217) for differentiating Alzheimer disease from other neurodegenerative disorders?
In this cross-sectional study that included 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated Alzheimer disease from other neurodegenerative diseases (area under the receiver operating characteristic curve of 0.89 in a neuropathologically defined cohort and 0.96 in a clinically defined cohort), with performance that was significantly better than established Alzheimer disease plasma- and MRI-based biomarkers but not significantly different from key CSF- or PET-based biomarkers.
Although plasma P-tau217 was able to discriminate Alzheimer disease from other neurodegenerative diseases, further research is needed to validate the findings in unselected and diverse populations, optimize the assay, and determine its potential role in clinical care.
There are limitations in current diagnostic testing approaches for Alzheimer disease (AD).
To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD.
Design, Setting, and Participants
Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017).
Main Outcomes and Measures
Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]).
Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P < .001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P > .15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ = 0.15; P = .33), β-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF Aβ42:Aβ40 ratio, and MRI measures (AUC range, 0.67-0.90; P < .05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P = .22).
Conclusions and Relevance
Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care.
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Corresponding Author: Oskar Hansson, MD, PhD, Memory Clinic, Skåne University Hospital, SE-20502 Malmö, Sweden (Oskar.Hansson@med.lu.se).
Accepted for Publication: June 22, 2020.
Published Online: July 28, 2020. doi:10.1001/jama.2020.12134
Author Contributions: Drs Hansson and Palmqvist had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Palmqvist and Janelidze contributed equally as first authors. Drs Hansson and Reiman (nonequally) contributed as senior authors.
Concept and design: Hansson.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Palmqvist, Janelidze, Hansson.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Palmqvist, Janelidze, Su, Chen, Strandberg.
Obtained funding: Palmqvist, Zetterberg, Mattsson-Carlgren, Beach, Blennow, Dage, Reiman, Hansson.
Administrative, technical, or material support: Palmqvist, Lopera, Strandberg, Smith, Villegas, Sepulveda-Falla, Chai, Beach, Dage, Reiman, Hansson.
Supervision: Dage, Reiman, Hansson.
Conflict of Interest Disclosures: Dr Quiroz reported receiving grants from the National Institutes of Health (NIH) and Massachusetts General Hospital. Dr Zetterberg reported receiving grants from The Knut and Alice Wallenberg Foundation, European Research Council, and Swedish Research Council; receiving personal fees from Samumed, Roche Diagnostics, CogRx, Wave, Alzecure, and Biogen; and that he is cofounder of Brain Biomarker Solutions in Gothenburg AB. Dr Lopera reported receiving grants from the NIH and Genentech/Roche/Banner and receiving personal fees from the NIH. Dr Su reported receiving grants from the NIH, the State of Arizona, BrightFocus Foundation, and Alzheimer's Association and receiving personal fees from Green Valley Pharmaceutical LLC. Dr Chai reported a patent to pTau217 assay and its use, antibodies pending. Dr Beach reported receiving grants from the State of Arizona; receiving personal fees from Prothena Biosciences, Vivid Genomics, and Avid Radiopharmaceuticals; and holding stock options with Vivid Genomics. Dr Blennow reported receiving personal fees from Abcam, Axon, Biogen, Lilly, MagQu, Novartis, and Roche Diagnostics and that he is cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. Dr Dage reported a patent pending for compounds and methods targeting human tau. Dr Reiman reported receiving grants from National Institute on Aging and the State of Arizona; receiving philanthropic funding from the Banner Alzheimer’s Foundation, Sun Health Foundation, and Roche/Roche Diagnostics; receiving personal fees from Alkahest, Alzheon, Aural Analytics, Denali, Green Valley, MagQ, Takeda/Zinfandel, United Neuroscience; that he has since submission of manuscript become a cofounder of AlzPath, which aims to further develop P-tau217 and fluid biomarkers and advance their use in research, drug development, and clinical settings; holding a patent owned by Banner Health for a strategy to use biomarkers to accelerate evaluation of Alzheimer prevention therapies; and that he is a principal investigator of prevention trials that include research agreements with Genentech/Roche and Novartis/Amgen, PET studies that include research agreements with Avid/Lilly, and several NIH and Foundation-supported research studies. Dr Hansson reported receiving grants from Roche, Biogen, and Pfizer and receiving nonfinancial support from GE Healthcare, AVID Radiopharmaceuticals, and Euroimmun. No other disclosures were reported.
Funding/Support: Work at the authors’ research centers was supported by the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Region Skåne, the Marianne and Marcus Wallenberg Foundation, the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, The Parkinson Foundation of Sweden, The Parkinson Research Foundation, the Skåne University Hospital Foundation, the Greta and Johan Kock Foundation, the Swedish federal government under the ALF agreement, the NIH Office of the Director, the Alzheimer’s Association, the Massachusetts General Hospital Executive Committee on Research, the National Institute of Neurological Disorders and Stroke (U24 NS072026), National Institute on Aging (P30 AG19610), the Arizona Department of Health Services, the Michael J. Fox Foundation for Parkinson’s Research, Banner Alzheimer’s Foundation, Sun Health Foundation, the State of Arizona, and Eli Lilly and Company. Eli Lilly and Company provided material support for P-tau217 sample analysis and salary for Dr Chai, Mr Proctor, and Dr Dage. The precursor of 18F-flutemetamol was provided by GE Healthcare and the precursor of 18F-RO948 was provided by Roche.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. In addition, Eli Lilly and company had the opportunity to review the manuscript before submission but had no veto power. Dr Hansson made the final decision to submit the manuscript to JAMA for publication.
Meeting Presentation: This study was presented online at the Alzheimer's Association International Conference; July 28, 2020.
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