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

Bruno Dubois; Nicolas Villain; Giovanni B Frisoni; Gil D Rabinovici; Marwan Sabbagh; Stefano Cappa; Alexandre Bejanin; Stéphanie Bombois; Stéphane Epelbaum; Marc Teichmann; Marie-Odile Habert; Agneta Nordberg; Kaj Blennow; Douglas Galasko; Yaakov Stern; Christopher C Rowe; Stephen Salloway; Lon S Schneider; Jeffrey L Cummings; Howard H Feldman

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

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

Lancet Neurol. 2021 Jun;20(6):484-496. doi: 10.1016/S1474-4422(21)00066-1. Epub 2021 Apr 29.

Authors

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

Alzheimer Disease / diagnosis*
Amyloid beta-Peptides / analysis
Amyloid beta-Peptides / metabolism
Biomarkers / analysis*
Cognitive Dysfunction / diagnosis
Disease Progression
Humans
Phenotype
tau Proteins / analysis
tau Proteins / metabolism

Substances

Amyloid beta-Peptides
Biomarkers
tau Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding