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Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer’s Disease Neuroimaging Initiative

Molecular Psychiatry volume 26, pages 429–442 (2021)Cite this article

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Abstract

Whilst cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers for amyloid-β (Aβ) and tau pathologies are accurate for the diagnosis of Alzheimer’s disease (AD), their broad implementation in clinical and trial settings are restricted by high cost and limited accessibility. Plasma phosphorylated-tau181 (p-tau181) is a promising blood-based biomarker that is specific for AD, correlates with cerebral Aβ and tau pathology, and predicts future cognitive decline. In this study, we report the performance of p-tau181 in >1000 individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD dementia patients characterized by Aβ PET. We confirmed that plasma p-tau181 is increased at the preclinical stage of Alzheimer and further increases in MCI and AD dementia. Individuals clinically classified as AD dementia but having negative Aβ PET scans show little increase but plasma p-tau181 is increased if CSF Aβ has already changed prior to Aβ PET changes. Despite being a multicenter study, plasma p-tau181 demonstrated high diagnostic accuracy to identify AD dementia (AUC = 85.3%; 95% CI, 81.4–89.2%), as well as to distinguish between Aβ− and Aβ+ individuals along the Alzheimer’s continuum (AUC = 76.9%; 95% CI, 74.0–79.8%). Higher baseline concentrations of plasma p-tau181 accurately predicted future dementia and performed comparably to the baseline prediction of CSF p-tau181. Longitudinal measurements of plasma p-tau181 revealed low intra-individual variability, which could be of potential benefit in disease-modifying trials seeking a measurable response to a therapeutic target. This study adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment.

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Fig. 1: Plasma p-tau181 profile.
Fig. 2: Cross-sectional associations at baseline.
Fig. 3: Plasma p-tau181 as a predictor.
Fig. 4: Longitudinal plasma p-tau181 profile.

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Data availability

The files used in preparing this manuscript are publicly available from http://adni.loni.usc.edu/. All data are available in the main text or the supplementary materials.

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Acknowledgements

Data collection and sharing was funded by ADNI (NIH #U01 AG024904) and DOD ADNI (#W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. TKK holds a Brightfocus fellowship (#A2020812F), and is further supported by the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-930627), the Swedish Brain Foundation (Hjärnfonden; #FO2020-0240), the Swedish Dementia Foundation (Demensförbundet), the Agneta Prytz-Folkes & Gösta Folkes Foundation (#2020-00124), the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Anna Lisa and Brother Björnsson’s Foundation, Gamla Tjänarinnor, and the Gun and Bertil Stohnes Foundation. NJA is supported by the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-931009), the Swedish Brain Foundation (Hjärnfonden), the Agneta Prytz-Folkes & Gösta Folkes Foundation, and the Swedish Dementia Foundation (Demensförbundet). AS was supported by the Emil Aaltonen Foundation and the Paulo Foundation, and currently receives funding from the Orion Research Foundation. MS-C received funding from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie action grant agreement No 752310, and currently receives funding from Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I). PR-N is supported by the Weston Brain Institute, the Canadian Institutes of Health Research, the Canadian Consortium on Neurodegeneration in Aging and the Fonds de Recherche du Québec—Santé (FRQS; Chercheur Boursier, and 2020-VICO-279314 TRIAD/BIOVIE Cohort), the CIHR-CCNA Canadian Consortium of Neurodegeneration in Aging, and the Canada Foundation for Innovation (project 34874). KB was supported by the Alzheimer Drug Discovery Foundation (ADDF; #RDAPB-201809-2016615), the Swedish Research Council (#2017-00915), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), and a grant (#ALFGBG-715986) from the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement. KB is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL.

Author information

Author notes

  1. These authors contributed equally: Thomas K. Karikari, Andréa L. Benedet, Nicholas J. Ashton

  2. These authors jointly supervised this work: John Q. Trojanowski, Leslie M. Shaw, Kaj Blennow, Henrik Zetterberg

Authors and Affiliations

  1. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden

    Thomas K. Karikari, Nicholas J. Ashton, Juan Lantero Rodriguez, Anniina Snellman, Hlin Kvartsberg, Alexis Moscoso Rial, Ulf Andreasson, Michael Schöll, Kaj Blennow & Henrik Zetterberg

  2. Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, H4H 1R3, Montreal, QC, Canada

    Andréa L. Benedet, Firoza Lussier, Tharick A. Pascoal & Pedro Rosa-Neto

  3. Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Mölndal, Sweden

    Nicholas J. Ashton, Alexis Moscoso Rial & Michael Schöll

  4. King’s College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, UK

    Nicholas J. Ashton

  5. NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, UK

    Nicholas J. Ashton

  6. Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, FI-20520, Turku, Finland

    Anniina Snellman

  7. Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain

    Marc Suárez-Calvet

  8. IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain

    Marc Suárez-Calvet

  9. Servei de Neurologia, Hospital del Mar, Barcelona, Spain

    Marc Suárez-Calvet

  10. Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain

    Marc Suárez-Calvet

  11. Department of Epidemiology and Biostatistics, McGill University, Montreal, QC, Canada

    Paramita Saha-Chaudhuri

  12. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

    Hlin Kvartsberg, Ulf Andreasson, Kaj Blennow & Henrik Zetterberg

  13. Montreal Neurological Institute, H3A 2B4, Montreal, QC, Canada

    Tharick A. Pascoal & Pedro Rosa-Neto

  14. Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK

    Michael Schöll & Henrik Zetterberg

  15. Department of Radiology, Medicine, and Psychiatry, University of California San Francisco, San Francisco, CA, USA

    Michael W. Weiner

  16. Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, QC, Canada

    Pedro Rosa-Neto

  17. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    John Q. Trojanowski

  18. Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    John Q. Trojanowski & Leslie M. Shaw

  19. UK Dementia Research Institute at UCL, London, UK

    Henrik Zetterberg

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  1. Thomas K. Karikari
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Contributions

TKK, ALB, NJA, PS-C, MWW, JQT, PR-N, LMS, KB, and HZ conceptualized the research; TKK, NJA, JLR, AS, MS-C, HK, UA, LMS, KB, and HZ performed plasma p-tau181 measurements, data quality control and data compilation; TKK, ALB, NJA, FL, PS-C, AMR, MS, TAP, PR-N, KB, and HZ contributed to data analysis; ALB, FL, PS-C, TAP and PR-N developed and implemented algorithms for data analysis; TKK, ALB, NJA, KB, and HZ wrote the original manuscript draft. All authors reviewed, edited, and approved the final manuscript for submission.

Corresponding author

Correspondence to Henrik Zetterberg.

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Conflict of interest

KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers. HZ has served at scientific advisory boards for Wave, Samumed, CogRx, Siemens Healthineers, and Roche Diagnostics and has given open lectures for Alzecure, Fujirebio, and Biogen. HZ and KB are co-founders of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. The other authors declare no competing interests.

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Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

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Karikari, T.K., Benedet, A.L., Ashton, N.J. et al. Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer’s Disease Neuroimaging Initiative. Mol Psychiatry 26, 429–442 (2021). https://doi.org/10.1038/s41380-020-00923-z

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