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Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders

Educational Objective
To learn the accuracy of plasma tau phosphorylated at threonine 217 (P-tau217) as a biomarker for Alzheimer disease (AD).
1 Credit CME
Key Points

Question  What is the discriminative accuracy of plasma phospho-tau217 (P-tau217) for differentiating Alzheimer disease from other neurodegenerative disorders?

Findings  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.

Meaning  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.

Abstract

Importance  There are limitations in current diagnostic testing approaches for Alzheimer disease (AD).

Objective  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).

Exposures  Plasma P-tau217.

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]).

Results  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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Article Information

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.

References
1.
Brookmeyer  R , Johnson  E , Ziegler-Graham  K , Arrighi  HM .  Forecasting the global burden of Alzheimer’s disease.   Alzheimers Dement. 2007;3(3):186-191. doi:10.1016/j.jalz.2007.04.381PubMedGoogle ScholarCrossref
2.
 Global Action Plan on the Public Health Response to Dementia 2017-2025. World Health Organization; 2017.
3.
Abbasi  J .  Promising results in 18-month analysis of Alzheimer drug candidate.   JAMA. 2018;320(10):965. doi:10.1001/jama.2018.13027PubMedGoogle Scholar
4.
Sevigny  J , Chiao  P , Bussière  T ,  et al.  The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease.   Nature. 2016;537(7618):50-56. doi:10.1038/nature19323PubMedGoogle ScholarCrossref
5.
Rabinovici  GD , Gatsonis  C , Apgar  C ,  et al.  Association of amyloid positron emission tomography with subsequent change in clinical management among Medicare beneficiaries with mild cognitive impairment or dementia.   JAMA. 2019;321(13):1286-1294. doi:10.1001/jama.2019.2000PubMedGoogle ScholarCrossref
6.
Ossenkoppele  R , Rabinovici  GD , Smith  R ,  et al.  Discriminative accuracy of [18F]flortaucipir positron emission tomography for Alzheimer disease vs other neurodegenerative disorders.   JAMA. 2018;320(11):1151-1162. doi:10.1001/jama.2018.12917PubMedGoogle ScholarCrossref
7.
Mattsson  N , Zetterberg  H , Hansson  O ,  et al.  CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment.   JAMA. 2009;302(4):385-393. doi:10.1001/jama.2009.1064PubMedGoogle ScholarCrossref
8.
Jack  CR  Jr , Bennett  DA , Blennow  K ,  et al.  NIA-AA research framework: toward a biological definition of Alzheimer’s disease.   Alzheimers Dement. 2018;14(4):535-562. doi:10.1016/j.jalz.2018.02.018PubMedGoogle ScholarCrossref
9.
Janelidze  S , Stomrud  E , Smith  R ,  et al.  Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease.   Nat Commun. 2020;11(1):1683. doi:10.1038/s41467-020-15436-0PubMedGoogle ScholarCrossref
10.
Duits  FH , Martinez-Lage  P , Paquet  C ,  et al.  Performance and complications of lumbar puncture in memory clinics: results of the multicenter lumbar puncture feasibility study.   Alzheimers Dement. 2016;12(2):154-163. doi:10.1016/j.jalz.2015.08.003PubMedGoogle ScholarCrossref
11.
Ovod  V , Ramsey  KN , Mawuenyega  KG ,  et al.  Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis.   Alzheimers Dement. 2017;13(8):841-849. doi:10.1016/j.jalz.2017.06.2266PubMedGoogle ScholarCrossref
12.
Palmqvist  S , Janelidze  S , Stomrud  E ,  et al.  Performance of fully automated plasma assays as screening tests for Alzheimer disease–related β-amyloid status.   JAMA Neurol. 2019;76(9):1060-1069. doi:10.1001/jamaneurol.2019.1632PubMedGoogle ScholarCrossref
13.
Janelidze  S , Mattsson  N , Palmqvist  S ,  et al.  Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia.   Nat Med. 2020;26(3):379-386. doi:10.1038/s41591-020-0755-1PubMedGoogle ScholarCrossref
14.
Thijssen  EH , La Joie  R , Wolf  A ,  et al; Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) Investigators.  Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration.   Nat Med. 2020;26(3):387-397. doi:10.1038/s41591-020-0762-2PubMedGoogle ScholarCrossref
15.
Beach  TG , Adler  CH , Sue  LI ,  et al.  Arizona study of aging and neurodegenerative disorders and brain and body donation program.   Neuropathology. 2015;35(4):354-389. doi:10.1111/neup.12189PubMedGoogle ScholarCrossref
16.
National Institute on Aging and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease.  Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease.   Neurobiol Aging. 1997;18(4)(suppl):S1-S2.PubMedGoogle ScholarCrossref
17.
Mirra  SS , Heyman  A , McKeel  D ,  et al.  The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), II: standardization of the neuropathologic assessment of Alzheimer’s disease.   Neurology. 1991;41(4):479-486. doi:10.1212/WNL.41.4.479PubMedGoogle ScholarCrossref
18.
Braak  H , Braak  E .  Neuropathological stageing of Alzheimer-related changes.   Acta Neuropathol. 1991;82(4):239-259. doi:10.1007/BF00308809PubMedGoogle ScholarCrossref
19.
 Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition). American Psychiatric Association; 2013.
20.
Tariot  PN , Lopera  F , Langbaum  JB ,  et al; Alzheimer’s Prevention Initiative.  The Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Trial: a study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer’s disease, including a placebo-treated noncarrier cohort.   Alzheimers Dement (N Y). 2018;4:150-160.PubMedGoogle Scholar
21.
Morris  JC , Heyman  A , Mohs  RC ,  et al.  The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), I: clinical and neuropsychological assessment of Alzheimer’s disease.   Neurology. 1989;39(9):1159-1165. doi:10.1212/WNL.39.9.1159PubMedGoogle ScholarCrossref
22.
Palmqvist  S , Insel  PS , Stomrud  E ,  et al.  Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer’s disease.   EMBO Mol Med. 2019;11(12):e11170. doi:10.15252/emmm.201911170PubMedGoogle Scholar
23.
Mielke  MM , Hagen  CE , Xu  J ,  et al.  Plasma phospho-tau181 increases with Alzheimer’s disease clinical severity and is associated with tau- and amyloid-positron emission tomography.   Alzheimers Dement. 2018;14(8):989-997. doi:10.1016/j.jalz.2018.02.013PubMedGoogle ScholarCrossref
24.
Leuzy  A , Smith  R , Ossenkoppele  R ,  et al.  Diagnostic performance of RO948 F 18 tau positron emission tomography in the differentiation of Alzheimer disease from other neurodegenerative disorders.   JAMA Neurol. Published online May 11, 2020. doi:10.1001/jamaneurol.2020.0989PubMedGoogle Scholar
25.
DeLong  ER , DeLong  DM , Clarke-Pearson  DL .  Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach.   Biometrics. 1988;44(3):837-845. doi:10.2307/2531595PubMedGoogle ScholarCrossref
26.
Quiroz  YT , Zetterberg  H , Reiman  EM ,  et al.  Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross-sectional and longitudinal cohort study.   Lancet Neurol. 2020;19(6):513-521. doi:10.1016/S1474-4422(20)30137-XPubMedGoogle ScholarCrossref
27.
Barthélemy  NR , Bateman  RJ , Hirtz  C ,  et al.  Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer’s disease and PET amyloid-positive patient identification.   Alzheimers Res Ther. 2020;12(1):26. doi:10.1186/s13195-020-00596-4PubMedGoogle ScholarCrossref
28.
Barthélemy  NR , Li  Y , Joseph-Mathurin  N ,  et al; Dominantly Inherited Alzheimer Network.  A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease.   Nat Med. 2020;26(3):398-407. doi:10.1038/s41591-020-0781-zPubMedGoogle ScholarCrossref
29.
Mattsson-Carlgren  N , Andersson  E , Janelidze  S ,  et al.  Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive tau PET in Alzheimer’s disease.   Sci Adv. 2020;6(16):eaaz2387. doi:10.1126/sciadv.aaz2387PubMedGoogle Scholar
30.
Mattsson  N , Zetterberg  H , Janelidze  S ,  et al; Alzheimer’s Disease Neuroimaging Initiative Investigators.  Plasma tau in Alzheimer disease.   Neurology. 2016;87(17):1827-1835. doi:10.1212/WNL.0000000000003246PubMedGoogle ScholarCrossref
31.
Palmqvist  S , Insel  PS , Zetterberg  H ,  et al; Alzheimer’s Disease Neuroimaging Initiative; Swedish BioFINDER study.  Accurate risk estimation of β-amyloid positivity to identify prodromal Alzheimer’s disease: cross-validation study of practical algorithms.   Alzheimers Dement. 2019;15(2):194-204. doi:10.1016/j.jalz.2018.08.014PubMedGoogle ScholarCrossref
32.
Zetterberg  H , Wilson  D , Andreasson  U ,  et al.  Plasma tau levels in Alzheimer’s disease.   Alzheimers Res Ther. 2013;5(2):9. doi:10.1186/alzrt163PubMedGoogle ScholarCrossref
33.
Chatterjee  P , Goozee  K , Sohrabi  HR ,  et al.  Association of plasma neurofilament light chain with neocortical amyloid-β load and cognitive performance in cognitively normal elderly participants.   J Alzheimers Dis. 2018;63(2):479-487. doi:10.3233/JAD-180025PubMedGoogle ScholarCrossref
34.
Mattsson  N , Andreasson  U , Zetterberg  H , Blennow  K ; Alzheimer’s Disease Neuroimaging Intiative.  Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease.   JAMA Neurol. 2017;74(5):557-566. doi:10.1001/jamaneurol.2016.6117PubMedGoogle ScholarCrossref
35.
Zhou  W , Zhang  J , Ye  F ,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Plasma neurofilament light chain levels in Alzheimer’s disease.   Neurosci Lett. 2017;650:60-64. doi:10.1016/j.neulet.2017.04.027PubMedGoogle ScholarCrossref
36.
Gordon  BA , Blazey  TM , Christensen  J ,  et al.  Tau PET in autosomal dominant Alzheimer’s disease: relationship with cognition, dementia and other biomarkers.   Brain. 2019;142(4):1063-1076. doi:10.1093/brain/awz019PubMedGoogle ScholarCrossref
37.
Quiroz  YT , Sperling  RA , Norton  DJ ,  et al.  Association between amyloid and tau accumulation in young adults with autosomal dominant Alzheimer disease.   JAMA Neurol. 2018;75(5):548-556. doi:10.1001/jamaneurol.2017.4907PubMedGoogle ScholarCrossref
38.
Sato  C , Barthelemy  NR , Mawuenyega  KG ,  et al  Tau kinetics in neurons and the human central nervous system.   Neuron. 2018;97(6):1284-1298.Google ScholarCrossref
39.
Kuhlmann  J , Andreasson  U , Pannee  J ,  et al; IFCC Working Group on Standardization of CSF proteins (WG-CSF).  CSF Aβ1-42—an excellent but complicated Alzheimer’s biomarker—a route to standardisation.   Clin Chim Acta. 2017;467:27-33. doi:10.1016/j.cca.2016.05.014PubMedGoogle ScholarCrossref
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