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Developing the ATX(N) classification for use across the Alzheimer disease continuum

Nature Reviews Neurology volume 17, pages 580–589 (2021)Cite this article

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Abstract

Breakthroughs in the development of highly accurate fluid and neuroimaging biomarkers have catalysed the conceptual transformation of Alzheimer disease (AD) from the traditional clinical symptom-based definition to a clinical–biological construct along a temporal continuum. The AT(N) system is a symptom-agnostic classification scheme that categorizes individuals using biomarkers that chart core AD pathophysiological features, namely the amyloid-β (Aβ) pathway (A), tau-mediated pathophysiology (T) and neurodegeneration (N). This biomarker matrix is now expanding towards an ATX(N) system, where X represents novel candidate biomarkers for additional pathophysiological mechanisms such as neuroimmune dysregulation, synaptic dysfunction and blood–brain barrier alterations. In this Perspective, we describe the conceptual framework and clinical importance of the existing AT(N) system and the evolving ATX(N) system. We provide a state-of-the-art summary of the potential contexts of use of these systems in AD clinical trials and future clinical practice. We also discuss current challenges related to the validation, standardization and qualification process and provide an outlook on the real-world application of the AT(N) system.

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Fig. 1: Temporal evolution of AD pathophysiology and biomarkers.
Fig. 2: The evolving ATX(N) system.

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Acknowledgements

J. L. C. is supported by KMA, NIGMS grant P20GM109025, NINDS grant U01NS093334 and NIA grant R01AG053798. K. B. 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, ALF-agreement (#ALFGBG-715986); and the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). C. R. J. receives research support from NIH (R37AG11378, P30AG62677, U01AG06786, U19AG32438, U19AG24904, R01AG41851, R01AG43392, W81XWH-13-1-0259, R01AG49704, R01NS92625, RF1AG50745, R01AG51406, R01AG54787, R01NS97495, R01AG53267, R01AG40282, R01AG54029, R01AG54449, R01AG54491, RF1AG55151, R01AG55469, R01AG55444, R01AG56366, U01AG57195, U24AG57437, ZEN-18-533411, RF1AG58729, R01AG58676, 18-PAF01312, R01AG59798, R01AG60502, JHS, R01AG61848, R01AG62689, R01AG63689, GC-201711-2014043, GC-201711-2014042, U01HL96812, U19NS115388 and U24AG67418) and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. The authors thank Dr Min Cho for his kind support in the critical revision of the article.

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Authors and Affiliations

  1. Neurology Business Group, Eisai Inc., Woodcliff Lake, NJ, USA

    Harald Hampel, Peng Gao & Andrea Vergallo

  2. Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas (UNLV), Las Vegas, NV, USA

    Jeffrey Cummings

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

    Kaj Blennow

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

    Kaj Blennow

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

    Clifford R. Jack Jr

Authors
  1. Harald Hampel
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  2. Jeffrey Cummings
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  3. Kaj Blennow
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  4. Peng Gao
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  5. Clifford R. Jack Jr
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  6. Andrea Vergallo
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Contributions

H. J. H. and A. V. developed the initial concept and theoretical framework for this article. All authors contributed to researching the literature and data for the article, discussing its content, and writing, reviewing and/or editing of the manuscript.

Corresponding author

Correspondence to Harald Hampel.

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Competing interests

H. H. is an employee of Eisai and serves as Senior Associate Editor for the journal Alzheimer’s & Dementia. He has not received any fees or honoraria since May 2019; before May 2019, he was a consultant and received lecture fees from Servier, Biogen and Roche, research grants from Pfizer, Avid and MSD Avenir (paid to the institution), travel funding from Eisai, Functional Neuromodulation, Axovant, Eli Lilly and Company, Takeda and Zinfandel, GE Healthcare and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox, Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics and Functional Neuromodulation, and participated in the scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and Company, Cytox, GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostics. He is co-inventor in the following patents as a scientific expert and has received no royalties: In Vitro Multiparameter Determination Method for the Diagnosis and Early Diagnosis of Neurodegenerative Disorders (patent no. 8916388); In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases (patent no. 8298784); Neurodegenerative Markers for Psychiatric Conditions (publication no. 20120196300); In Vitro Multiparameter Determination Method for the Diagnosis and Early Diagnosis of Neurodegenerative Disorders (publication no. 20100062463); In Vitro Method for the Diagnosis and Early Diagnosis of Neurodegenerative Disorders (publication no. 20100035286); In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases (publication no. 20090263822); In Vitro Method for the Diagnosis of Neurodegenerative Diseases (patent no. 7547553); CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases (publication no. 20080206797); In Vitro Method for the Diagnosis of Neurodegenerative Diseases (publication no. 20080199966); Neurodegenerative Markers for Psychiatric Conditions (publication no. 20080131921); and Method for Diagnosis of Dementias and Neuroinflammatory Diseases Based on an Increased Level of Procalcitonin in Cerebrospinal Fluid (publication no. US Patent 10921330). J. C. has provided consultation to Acadia, Actinogen, Alkahest, Alzheon, AnnovisBio, Avanir, Axsome, BiOasis, Biogen, Cassava, Cerecin, Cortexyme, Cytox, Diadem, EIP Pharma, Eisai, Foresight, GemVax, Genentech, Green Valley, Grifols, Maplight, Merck, Otsuka, Resverlogix, Roche, Samumed, Samus, Signant, Third Rock, and United Neuroscience pharmaceutical and assessment companies. He has stock options in ADAMAS, MedAvante, QR pharma/AnnovisBio, and BiOasis. K. B. has served as a consultant, on advisory boards or on data monitoring committees for Abcam, Axon, Biogen, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is part of the GU Ventures Incubator Program. C. R. J. serves on an independent data monitoring board for Roche and is a speaker for Eisai but receives no personal compensation from any commercial entity. P. G. is an employee of Eisai. A. V. is an employee of Eisai. He has not received any fees or honoraria since November 2019. Before November 2019, he received lecture honoraria from Roche, MagQu LLC and Servier.

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Nature Reviews Neurology thanks T. Benzinger, who co-reviewed with C. Chen, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Hampel, H., Cummings, J., Blennow, K. et al. Developing the ATX(N) classification for use across the Alzheimer disease continuum. Nat Rev Neurol 17, 580–589 (2021). https://doi.org/10.1038/s41582-021-00520-w

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