Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group

doi:10.1016/S1474-4422(21)00066-1

Review

. 2021 Jun;20(6):484-496.

doi: 10.1016/S1474-4422(21)00066-1. Epub 2021 Apr 29.

Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group

Bruno Dubois¹, Nicolas Villain², Giovanni B Frisoni³, Gil D Rabinovici⁴, Marwan Sabbagh⁵, Stefano Cappa⁶, Alexandre Bejanin⁷, Stéphanie Bombois⁸, Stéphane Epelbaum⁹, Marc Teichmann¹⁰, Marie-Odile Habert¹¹, Agneta Nordberg¹², Kaj Blennow¹³, Douglas Galasko¹⁴, Yaakov Stern¹⁵, Christopher C Rowe¹⁶, Stephen Salloway¹⁷, Lon S Schneider¹⁸, Jeffrey L Cummings¹⁹, Howard H Feldman²⁰

Affiliations

¹ Assistance Publique-Hôpitaux de Paris (AP-HP) Department of Neurology, Sorbonne University, Paris, France; Institut du Cerveau, Sorbonne University, Paris, France. Electronic address: bruno.dubois@aphp.fr.
² Assistance Publique-Hôpitaux de Paris (AP-HP) Department of Neurology, Sorbonne University, Paris, France; Institut du Cerveau, Sorbonne University, Paris, France.
³ Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland; Memory Clinic, University Hospital of Geneva, Geneva, Switzerland; Laboratory of Alzheimer's Neuroimaging and Epidemiology (LANE), Saint John of God Clinical Research Centre, Brescia, Italy.
⁴ Memory and Aging Center, Department of Neurology and Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.
⁵ Cleveland Clinic, Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.
⁶ University School for Advanced Studies, Pavia, Italy; RCCS Mondino Foundation, Pavia, Italy.
⁷ Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain; Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain; Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
⁸ Assistance Publique-Hôpitaux de Paris (AP-HP) Department of Neurology, Sorbonne University, Paris, France; INSERM, CHU Lille, U1171 - Degenerative and vascular cognitive disorders, University of Lille, Lille, France.
⁹ Assistance Publique-Hôpitaux de Paris (AP-HP) Department of Neurology, Sorbonne University, Paris, France; Inria ARAMIS project team, Inria-APHP collaboratio, Sorbonne University, Paris, France; Institut du Cerveau, Sorbonne University, Paris, France.
¹⁰ Assistance Publique-Hôpitaux de Paris (AP-HP) Department of Neurology, Sorbonne University, Paris, France.
¹¹ AP-HP Department of Nuclear Medicine, Sorbonne University, Paris, France; CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, Sorbonne University, Paris, France; Institut du Cerveau, Sorbonne University, Paris, France.
¹² Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institute, Stockholm, Sweden; Theme Aging, The Aging Brain, Karolinska University Hospital, Stockholm, Sweden.
¹³ Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹⁴ Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
¹⁵ Cognitive Neuroscience Division, Department of Neurology, Columbia University, New York, NY, USA.
¹⁶ Department of Molecular Imaging and Therapy, Austin Health, The University of Melbourne, Melbourne, VIC, Australia.
¹⁷ Department of Neurology and Department of Psychiatry, Alpert Medical School of Brown University, Providence, RI, USA; Butler Hospital, Providence, RI, USA.
¹⁸ Keck School of Medicine of the University of Southern California, Los Angeles, USA.
¹⁹ Cleveland Clinic, Lou Ruvo Center for Brain Health, Las Vegas, NV, USA; Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, NV, USA.
²⁰ Department of Neurosciences, University of California San Diego, La Jolla, CA, USA; Shiley-Marcos Alzheimer's Disease Research Center, University of California San Diego, La Jolla, CA, USA; Alzheimer Disease Cooperative Study, University of California San Diego, La Jolla, CA, USA.

PMID: 33933186
PMCID: PMC8339877
DOI: 10.1016/S1474-4422(21)00066-1

Review

Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group

Bruno Dubois et al. Lancet Neurol. 2021 Jun.

. 2021 Jun;20(6):484-496.

doi: 10.1016/S1474-4422(21)00066-1. Epub 2021 Apr 29.

Authors

Affiliations

¹ Assistance Publique-Hôpitaux de Paris (AP-HP) Department of Neurology, Sorbonne University, Paris, France; Institut du Cerveau, Sorbonne University, Paris, France. Electronic address: bruno.dubois@aphp.fr.
² Assistance Publique-Hôpitaux de Paris (AP-HP) Department of Neurology, Sorbonne University, Paris, France; Institut du Cerveau, Sorbonne University, Paris, France.
³ Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland; Memory Clinic, University Hospital of Geneva, Geneva, Switzerland; Laboratory of Alzheimer's Neuroimaging and Epidemiology (LANE), Saint John of God Clinical Research Centre, Brescia, Italy.
⁴ Memory and Aging Center, Department of Neurology and Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.
⁵ Cleveland Clinic, Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.
⁶ University School for Advanced Studies, Pavia, Italy; RCCS Mondino Foundation, Pavia, Italy.
⁷ Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain; Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain; Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
⁸ Assistance Publique-Hôpitaux de Paris (AP-HP) Department of Neurology, Sorbonne University, Paris, France; INSERM, CHU Lille, U1171 - Degenerative and vascular cognitive disorders, University of Lille, Lille, France.
⁹ Assistance Publique-Hôpitaux de Paris (AP-HP) Department of Neurology, Sorbonne University, Paris, France; Inria ARAMIS project team, Inria-APHP collaboratio, Sorbonne University, Paris, France; Institut du Cerveau, Sorbonne University, Paris, France.
¹⁰ Assistance Publique-Hôpitaux de Paris (AP-HP) Department of Neurology, Sorbonne University, Paris, France.
¹¹ AP-HP Department of Nuclear Medicine, Sorbonne University, Paris, France; CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, Sorbonne University, Paris, France; Institut du Cerveau, Sorbonne University, Paris, France.
¹² Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institute, Stockholm, Sweden; Theme Aging, The Aging Brain, Karolinska University Hospital, Stockholm, Sweden.
¹³ Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹⁴ Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
¹⁵ Cognitive Neuroscience Division, Department of Neurology, Columbia University, New York, NY, USA.
¹⁶ Department of Molecular Imaging and Therapy, Austin Health, The University of Melbourne, Melbourne, VIC, Australia.
¹⁷ Department of Neurology and Department of Psychiatry, Alpert Medical School of Brown University, Providence, RI, USA; Butler Hospital, Providence, RI, USA.
¹⁸ Keck School of Medicine of the University of Southern California, Los Angeles, USA.
¹⁹ Cleveland Clinic, Lou Ruvo Center for Brain Health, Las Vegas, NV, USA; Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, NV, USA.
²⁰ Department of Neurosciences, University of California San Diego, La Jolla, CA, USA; Shiley-Marcos Alzheimer's Disease Research Center, University of California San Diego, La Jolla, CA, USA; Alzheimer Disease Cooperative Study, University of California San Diego, La Jolla, CA, USA.

PMID: 33933186
PMCID: PMC8339877
DOI: 10.1016/S1474-4422(21)00066-1

Abstract

In 2018, the US National Institute on Aging and the Alzheimer's Association proposed a purely biological definition of Alzheimer's disease that relies on biomarkers. Although the intended use of this framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. Furthermore, a positive Alzheimer's disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer's disease pathology is present as a comorbidity. In this Personal View, the International Working Group presents what we consider to be the current limitations of biomarkers in the diagnosis of Alzheimer's disease and, on the basis of this evidence, we propose recommendations for how biomarkers should and should not be used for diagnosing Alzheimer's disease in a clinical setting. We recommend that Alzheimer's disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer's disease phenotypes, whereas biomarker-positive cognitively unimpaired individuals should be considered only at-risk for progression to Alzheimer's disease.

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Conflict of interest statement

Declaration of interests BD reports personal fees from Biogen and grants paid to his institution from Roche, Merck-Avenir Foundation, and Fondation Recherche sur Alzheimer, outside the submitted work. NV reports grants from Fondation Recherche Alzheimer, Département Médical Universitaire APHP–Sorbonne Université, and non-financial support from GE Healthcare, Merz Pharma, UCB Pharma, Medtronic, and Laboratoire Aguettant, outside the submitted work. GDR reports grants from US National Institutes of Health (NIH)–National Institute on Aging (NIA), Alzheimer's Association, and Rainwater Charitable Foundation during the study; grants from Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare, Life Molecular Imaging, American College of Radiology, Genentech, and Roche; and personal fees from Eisai, Merck, Johnson & Johnson, Genentech, Roche, Avid Radiopharmaceuticals, GE Healthcare, and Axon Neurosciences, outside the submitted work; and is an Associate Editor of JAMA Neurology. MS reports personal fees from Allergan, Biogen, Grifols, vTv therapeutics, Sanofi, Neurotrope, Cortexyme; stock options from uMethod Health, Brain Health, Versanum, Optimal Cognitive Health Company; and stocks from Athira, outside the submitted work. SC reports personal fees from Biogen, Roche, and Nutricia, outside the submitted work. SE reports personal fees from Biogen, Roche, and GE Healthcare, outside the submitted work. M-OH reports personal fees from Blue Earth, outside the submitted work. AN reports personal fees from Roche, outside the submitted work. KB reports personal fees from Abcam, Axon Neuroscience, Biogen, Lilly, MagQu, Novartis, Roche Diagnostics, JOMDD/Shimadzu, Julius Clinical, and Siemens Healthineers, outside the submitted work, and is co-founder of Brain Biomarker Solutions in Gothenburg, a GU Ventures platform company at the University of Gothenburg, Sweden. DG reports personal fees from Biogen, vTv Pharmaceuticals, Fujirebio, and Springer; and grants from NIA and the Alzheimer's Drug Discovery Foundation, outside the submitted work. YS reports grants from NIA, and personal fees from Eisai and Takeda, outside the submitted work. CCR reports grants from Cerveau Technologies, Eisai, NHMRC Australia, and US Department of Defense; and personal fees from Biogen and Cerveau Technologies, outside the submitted work. SS reports grants from Biogen, Eisai, and Avid; personal fees from Biogen, Eisai, Avid, Novartis, Lilly, Genentech, and Roche; and non-financial support from Biogen, Avid, Novartis, Lilly, and Roche, outside the submitted work. LSS reports grants from Eli Lilly, Merck, Roche/Genentech, Biogen, Novartis, Biohaven, Washington University–NIA for the Dominantly Inherited Alzheimer Network Trial, and personal fees from Samus, Eli Lilly, Avraham, Boehringer Ingelheim, Merck, Neurim, Neuronix, Cognition, Eisai, Takeda, vTv, Roche/Genentech, Abbott, and Samus, outside the submitted work. JLC reports grants from NIH–US National Institute of General Medical Sciences, NIH, and NIH–US National Institute of Neurological Disorders and Stroke, during the study; personal fees from Acadia, Actinogen, AgeneBio, Alkahest, Alzheon, Annovis, Avanir, Axsome, Biogen, Cassava, Cerecin, Cerevel, Cognoptix, Cortexyme, EIP Pharma, Eisai, Foresight, Green Valley, Grifols, Karuna, Nutricia, Orion, Otsuka, Probiodrug, ReMYND, Resverlogix, Roche, Samumed, Samus Therapeutics, Third Rock, Signant Health, Sunovion, Suven, and United Neuroscience pharmaceutical and assessment companies; personal fees from Alzheimer Drug Discovery Foundation; and stock ownership from ADAMAS, BioAsis, MedAvante, QR Pharma, and United Neuroscience, outside the submitted work; JLC has a patent Neuropsychiatric Inventory with royalties paid, and is Chief Scientific Advisor of CNS Innovations. HHF reports grants to University of California San Diego (UCSD) from Toyama Pharmaceuticals, Biohaven Pharmaceuticals, Annovis (QR Pharma), AC Immune, Vivoryon Therapeutics (Probiodrug), and LuMind; service agreements via UCSD for consulting with Novo Nordisk, Eisai Pharmaceuticals, Merck Pharmaceuticals, Samus Therapeutics, Arkuda Therapeutics, Samumed, and Axon Neurosciences; institutional service agreements to serve on a data monitoring committee and data and safety monitoring board for Roche/Genentech Pharmaceuticals and Janssen Research & Development; serves on the scientific advisory board for the Tau Consortium; and reports travel expenses paid to his institution from World Events Forum (ADDF), Samus, Samumed, Axon, and Novo Nordisk, outside the submitted work. All other authors declare no competing interests.

Comment in

The changing definition of Alzheimer's disease.
Jagust WJ. Jagust WJ. Lancet Neurol. 2021 Jun;20(6):414-415. doi: 10.1016/S1474-4422(21)00077-6. Epub 2021 Apr 29. Lancet Neurol. 2021. PMID: 33933185 No abstract available.

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References

1. 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: 535–62. - PMC - PubMed
1. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EMM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS–ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34: 939–44. - PubMed
1. Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS–ADRDA criteria. Lancet Neurol 2007; 6: 734–46. - PubMed
1. Dubois B, Feldman HH, Jacova C, et al. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 2010; 9: 1118–27. - PubMed
1. Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 270–79. - PMC - PubMed

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[1] 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: 535–62. - PMC - PubMed

[2] 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: 535–62. - PMC - PubMed

[3] McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EMM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS–ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34: 939–44. - PubMed

[4] McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EMM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS–ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34: 939–44. - PubMed

[5] Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS–ADRDA criteria. Lancet Neurol 2007; 6: 734–46. - PubMed

[6] Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS–ADRDA criteria. Lancet Neurol 2007; 6: 734–46. - PubMed

[7] Dubois B, Feldman HH, Jacova C, et al. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 2010; 9: 1118–27. - PubMed

[8] Dubois B, Feldman HH, Jacova C, et al. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 2010; 9: 1118–27. - PubMed

[9] Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 270–79. - PMC - PubMed

[10] Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 270–79. - PMC - PubMed

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Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group

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Clinical diagnosis of Alzheimer's disease: recommendations of the International Working Group

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