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Biomarker-based staging of Alzheimer disease: rationale and clinical applications

Nature Reviews Neurology volume 20, pages 232–244 (2024)Cite this article

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Abstract

Disease staging, whereby the spatial extent and load of brain pathology are used to estimate the severity of Alzheimer disease (AD), is pivotal to the gold-standard neuropathological diagnosis of AD. Current in vivo diagnostic frameworks for AD are based on abnormal concentrations of amyloid-β and tau in the cerebrospinal fluid or on PET scans, and breakthroughs in molecular imaging have opened up the possibility of in vivo staging of AD. Focusing on the key principles of disease staging shared across several areas of medicine, this Review highlights the potential for in vivo staging of AD to transform our understanding of preclinical AD, refine enrolment criteria for trials of disease-modifying therapies and aid clinical decision-making in the era of anti-amyloid therapeutics. We provide a state-of-the-art review of recent biomarker-based AD staging systems and highlight their contributions to the understanding of the natural history of AD. Furthermore, we outline hypothetical frameworks to stage AD severity using more accessible fluid biomarkers. In addition, by applying amyloid PET-based staging to recently published anti-amyloid therapeutic trials, we highlight how biomarker-based disease staging frameworks could illustrate the numerous pathological changes that have already taken place in individuals with mildly symptomatic AD. Finally, we discuss challenges related to the validation and standardization of disease staging and provide a forward-looking perspective on potential clinical applications.

Key points

  • Disease staging systems are used across medicine to measure disease severity, estimate patient prognosis, determine eligibility for clinical trials and guide clinical care.

  • Staging systems provide a model of the natural history of a disease as well as a framework to validate new biomarkers and test new interventions.

  • Alzheimer disease (AD) has a long preclinical phase in which multiple biological changes are observable in the absence of symptoms; biomarker-based staging systems are well suited to detect and monitor these changes over the natural history of AD.

  • Biomarker-based staging using the topography of PET ligand uptake provides information about AD severity and aids prediction of clinical outcomes.

  • Recent work has highlighted the potential of fluid biomarker panels for the staging of AD and the development of plasma biomarker panels will substantially increase the accessibility of biomarker-based AD staging.

  • Biomarker-based AD staging might help to guide clinical decision-making; for example, evidence suggests that individuals with lower levels of tau tracer uptake on PET respond better to anti-amyloid monoclonal antibody therapy.

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Fig. 1: In vivo clinical and biomarker changes in relation to AD severity.
Fig. 2: Hypothetical fluid-based AD staging procedure.
Fig. 3: Biomarker-based staging and clinical trials.

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Acknowledgements

The authors thank Kelsey Caetano-Anolles for support with manuscript review. The TRIAD cohort (data in Fig. 3) is supported by the Weston Brain Institute, Canadian Institutes of Health Research (CIHR; grants MOP-11-51-31 and RFN 152985, 159815 and 162303), Canadian Consortium of Neurodegeneration and Aging (CCNA; MOP-11-51-31 team 1), the Alzheimer’s Association (grants NIRG-12-92090 and NIRP-12-259245), Brain Canada Foundation (CFI Project 34874; 33397), the Fonds de Recherche du Québec — Santé (FRQS; Chercheur Boursier, 2020-VICO-279314) and the Colin J. Adair Charitable Foundation.

Author information

Authors and Affiliations

  1. Translational Neuroimaging Laboratory, McGill Research Centre for Studies in Aging, Alzheimer’s Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-Montréal, Montreal, Quebec, Canada

    Joseph Therriault, Serge Gauthier & Pedro Rosa-Neto

  2. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada

    Joseph Therriault, Serge Gauthier & Pedro Rosa-Neto

  3. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA

    Suzanne E. Schindler & Randall J. Bateman

  4. Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA

    Suzanne E. Schindler & Randall J. Bateman

  5. Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden

    Gemma Salvadó, Jacob W. Vogel & Oskar Hansson

  6. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    Tharick A. Pascoal & Thomas K. Karikari

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

    Andréa Lessa Benedet, Nicholas J. Ashton, Thomas K. Karikari, Henrik Zetterberg & Kaj Blennow

  8. NIHR Biomedical Research Centre, South London and Maudsley NHS Foundation, London, UK

    Nicholas J. Ashton

  9. Department of Neurology, University of Indiana School of Medicine, Indianapolis, IN, USA

    Liana Apostolova

  10. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

    Melissa E. Murray

  11. Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam, Netherlands

    Inge Verberk & Charlotte Teunissen

  12. Department of Clinical Sciences, Malmö, SciLifeLab, Lund University, Lund, Sweden

    Jacob W. Vogel

  13. Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA

    Renaud La Joie & Gil D. Rabinovici

  14. Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA

    Gil D. Rabinovici

  15. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden

    Henrik Zetterberg

  16. Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK

    Henrik Zetterberg

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

    Henrik Zetterberg

  18. Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China

    Henrik Zetterberg

  19. Tracy Family SILQ Center, Washington University School of Medicine, St. Louis, MO, USA

    Randall J. Bateman

  20. Alzheimer Centre Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands

    Philip Scheltens

  21. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Reisa Sperling

  22. Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Reisa Sperling

  23. Memory Clinic, Skåne University Hospital, Malmö, Sweden

    Oskar Hansson

  24. Department of Radiology, Mayo Clinic, Rochester, MN, USA

    Clifford R. Jack Jr

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  1. Joseph Therriault
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Contributions

J.T., S.E.S., G.S., A.L.B., N.J.A., T.K.K., J.W.V., R.LJ., H.Z., C.R.J. and P.R.-N. researched the data for the article. J.T., S.E.S., G.S., T.A.P., A.L.B., N.J.A., T.K.K., L.A., I.V., J.W.V., R.LJ., C.T., G.D.R., H.Z., R.J.B., R.S., O.H., C.R.J. and P.R.-N. contributed substantially to discussion of the content. J.T., S.E.S., G.S., A.L.B., N.J.A., T.K.K., J.W.V., R.LJ., O.H., C.R.J. and P.R.-N. wrote the article. J.T., S.E.S., G.S., T.A.P., A.L.B., N.J.A., T.K.K., L.A., M.E.M., I.V., J.W.V., S.G., C.T., G.D.R., H.Z., R.J.B, P.S., K.B., R.S., O.H., C.R.J. and P.R.-N. reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Joseph Therriault.

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Competing interests

J.T. has received consultancy fees from the Neurotorium educational platform outside the scope of the present work. L.A. has received grants from the National Institute on Aging, the Alzheimer’s Association, AVID Radiopharmaceuticals, Life Molecular Imaging, and Roche Diagnostics and personal fees from Eli Lilly, Biogen, Two Labs, IQVIA, Genentech, Siemens, Corium, GE Healthcare, Eisai, Roche Diagnostics, Alnylam, the Alzheimer’s Association, and from the FDA outside the submitted work. C.T. reports non-financial support from Quanterix during the conduct of the study, has a patent pending for glial fibrillary acidic protein as a biomarker, serves as an editorial board member of Alzheimer’s Research and Therapy, Medidact Neurologie (Springer), and Neurology: Neuroimmunology & Neuroinflammation, serves as an editor of the Neuromethods book series (Springer), and reports grants from Roche Diagnostics, non-financial support from ADx Neurosciences and Eli Lilly, and compensation from AC Immune, Axon Neurosciences, Biogen, Brainstorm Cell Therapeutics, Celgene, Denali Therapeutics, EIP Pharma, Eisai, PeopleBio, Toyama Pharmaceutical Association and Vivoryon Therapeutics outside the submitted work. G.D.R. has received grants from the American College of Radiology, Avid Radiopharmaceuticals, Life Molecular Imaging (formerly Piramal Imaging) and GE Healthcare during the conduct of the study, personal fees from Alector, Eli Lilly, Merck, and the Johnson & Johnson Data and Safety Monitoring Board and grants from Genentech, the NIH, the Alzheimer’s Association, and Rainwater Charitable Foundation outside the submitted work, and is an Associate Editor for JAMA Neurology. R.J.B. declares research funding from Avid Radiopharmaceuticals, Janssen, Roche/Genentech, Eli Lilly, Eisai, Biogen, AbbVie, Bristol Myers Squibb and Novartis, equity ownership interest in C2N Diagnostics and income from C2N Diagnostics for serving on the scientific advisory board, serves on the Roche gantenerumab steering committee as an unpaid member, has income based on technology (blood plasma assay and methods of diagnosing Alzheimer disease with phosphorylation changes) licensed by Washington University to C2N Diagnostics, and also declares involvement with the Alzheimer’s Association, Duke Margolis Alzheimer’s, BrightFocus Foundation and Tau Consortium Investigators’ Meeting. H.Z. has served on scientific advisory boards and/or as a consultant for 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, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside the submitted work). P.S. is a full-time employee of EQT Life Sciences (formerly LSP) and Professor Emeritus at Amsterdam University Medical Centers. He has received consultancy fees (paid to the university) from Alzheon, Brainstorm Cell and Green Valley. Within his university affiliation, he was the global Principal Investigator of a phase Ib study for AC Immune, a phase IIb study for FUJI-film/Toyama and a phase II study for UCB. He is past chair of the European Union steering committee of the Vivoryon phase IIb programme and a phase IIb study for Novartis Cardiology, and is currently co-chair of a phase III study for Novo Nordisk. K.B. has served as a consultant and on advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Julius Clinical, Lilly, Novartis, Ono Pharma, Prothena, Roche Diagnostics and Siemens Healthineers, has served on data monitoring committees for Julius Clinical and Novartis, has given lectures, produced educational materials and participated in educational programmes for Biogen, Eisai and Roche Diagnostics, and is a co-founder of BBS, which is part of the GU Ventures Incubator Program, outside the work presented in this paper. R.S. reports grant support from the NIH, Eli Lilly, the Alzheimer’s Association, GHR Foundation, Fidelity, and Gates Ventures, non-financial support from CogState and Mount Sinai, grants and personal fees from Janssen, and personal fees from AC Immune, Biogen, Neurocentria, Eisai, Roche, Takeda and Novartis. O.H. has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer and Roche. In the past 2 years, he has received consultancy or speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens. P.R.-N. has served on scientific advisory boards and/or as a consultant for Roche, Novo Nordisk, Eisai and Cerveau Technologies. The other authors declare no competing interests.

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Therriault, J., Schindler, S.E., Salvadó, G. et al. Biomarker-based staging of Alzheimer disease: rationale and clinical applications. Nat Rev Neurol 20, 232–244 (2024). https://doi.org/10.1038/s41582-024-00942-2

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  • DOI: https://doi.org/10.1038/s41582-024-00942-2

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