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Mapping CSF biomarker profiles onto NIA–AA guidelines for Alzheimer’s disease

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Abstract

The National Institute on Aging–Alzheimer’s Association (NIA–AA) guidelines for Alzheimer’s disease (AD) propose the categorization of individuals according to their biomarker constellation. Though the NIA–AA criteria for preclinical AD and AD dementia have already been applied in conjunction with imaging AD biomarkers, the application of the criteria using comprehensive cerebrospinal fluid (CSF) biomarker information has not been thoroughly studied yet. The study included a monocentric cohort with healthy (N = 41) and disease (N = 22) controls and patients with AD dementia (N = 119), and a multicentric sample with healthy controls (N = 116) and patients with AD dementia (N = 102). The CSF biomarkers β-amyloid 1–42, total tau, and phosphorylated tau at threonine 181 were measured with commercially available assays. Biomarker values were trichotomized into positive for AD, negative, or borderline. In controls the presence of normal CSF profiles varied between 13.6 and 25.4 % across the studied groups, while up to 8.6 % of them had abnormal CSF biomarkers. In 40.3–52.9 % of patients with AD dementia, a typical CSF profile for AD was detected. Approximately 40 % of the potential biomarker constellations are not considered in the NIA–AA guidelines, and more than 40 % of participants could not be classified into the NIA–AA categories with distinct biomarker constellations. Here, a refined scheme covering all potential biomarker constellations is proposed. These results enrich the discussion on the NIA–AA guidelines and point to a discordance between clinical symptomatology and CSF biomarkers even in patients with full-blown AD dementia, who are supposed to have a clearly positive for AD neurochemical profile.

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Acknowledgments

The authors wish to express their gratitude to Ms. Tamara Eisele (Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar) for her excellent technical assistance.

Study funding

Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense Award Number 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: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; 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.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. 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.

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    Authors and Affiliations

    1. Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

      Panagiotis Alexopoulos, Jennifer Roesler, Nathalie Thierjung, Lukas Werle, Lena Gleixner, Marion Ortner, Timo Grimmer, Alexander Kurz & Robert Perneczky

    2. Department of Psychiatry, University Hospital of Rion, University of Patras, 26500, Rion, Patras, Greece

      Panagiotis Alexopoulos

    3. Max Planck Institute of Psychiatry, 80804, Munich, Germany

      Lukas Werle

    4. Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

      Dorothea Buck

    5. Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

      Igor Yakushev

    6. Department of Anaesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

      Simone Kagerbauer & Jan Martin

    7. Department of Urology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

      Hubert Kübler

    8. Department of Informatics, Aristotle University of Thessaloniki, Thessaloníki, Greece

      Nikolaos Laskaris

    9. Neuroepidemiology and Ageing Research Unit, Faculty of Medicine, School of Public Health, The Imperial College of Science, Technology and Medicine, London, UK

      Robert Perneczky

    10. West London Cognitive Disorders Treatment and Research Unit, West London Mental Health Trust, London, UK

      Robert Perneczky

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    1. Panagiotis Alexopoulos
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    Correspondence to Panagiotis Alexopoulos.

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    Conflict of interest

    Dr. Alexopoulos serves on the editorial board of the Journal of Alzheimer’s Disease and has received speaker honoraria from IBL International. Dr. Buck has received compensation for activities with Bayer HealthCare, BiogenIdec, MerckSerono, and Novartis. She was supported by the Commission for Clinical Research of the Faculty of Medicine, Technische Universität München, Abirisk and the PML Consortium. All other authors report no disclosures.

    Additional information

    For the Alzheimer’s Disease Neuroimaging Initiative. 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.

    Panagiotis Alexopoulos and Jennifer Roesler have contributed equally to the manuscript.

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    Alexopoulos, P., Roesler, J., Thierjung, N. et al. Mapping CSF biomarker profiles onto NIA–AA guidelines for Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 266, 587–597 (2016). https://doi.org/10.1007/s00406-015-0628-7

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