Alzheimer Disease as a Clinical-Biological Construct—An International Working Group Recommendation
Bruno Dubois
(1)
,
Nicolas Villain
(1)
,
Lon Schneider
(2)
,
Nick Fox
(3)
,
Noll Campbell
(4)
,
Douglas Galasko
(5)
,
Miia Kivipelto
(6)
,
Frank Jessen
(7)
,
Bernard Hanseeuw
(8)
,
Mercè Boada
(9)
,
Frederik Barkhof
(10)
,
Agneta Nordberg
(11)
,
Lutz Froelich
(12)
,
Gunhild Waldemar
(13)
,
Kristian Steen Frederiksen
(13)
,
Alessandro Padovani
(14)
,
Vincent Planche
(15)
,
Christopher Rowe
(16)
,
Alexandre Bejanin
(17)
,
Agustin Ibanez
(18)
,
Stefano Cappa
(19)
,
Paulo Caramelli
(20)
,
Ricardo Nitrini
(21)
,
Ricardo Allegri
(22)
,
Andrea Slachevsky
(23)
,
Leonardo Cruz de Souza
(24)
,
Andrea Bozoki
(25)
,
Eric Widera
(26)
,
Kaj Blennow
(27)
,
Craig Ritchie
(28)
,
Marc Agronin
(29)
,
Francisco Lopera
(30)
,
Lisa Delano-Wood
(31)
,
Stéphanie Bombois
(32)
,
Richard Levy
(1)
,
Madhav Thambisetty
(33)
,
Jean Georges
(34)
,
David T Jones
(35)
,
Helen Lavretsky
(36)
,
Jonathan Schott
(37)
,
Jennifer Gatchel
(38)
,
Sandra Swantek
(39)
,
Paul Newhouse
(40)
,
Howard H Feldman
(41)
,
Giovanni B Frisoni
(42)
1
FRONTlab -
Equipe Fonctions et dysfonctions de systèmes frontaux [ICM Paris]
2 4. Keck School of Medicine of the University of Southern California, Los Angeles, USA
3 Dementia Research Centre, Department of Neurodegenerative Disease, and the UK Dementia Research Institute, UCL Queen Square Institute of Neurology, London WC1N 3AR, UK
4 Purdue University Center for Aging and the Life Course, West Lafayette, Indiana, USA
5 Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA
6 Center for Alzheimer Research, Karolinska Institutet, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden
7 Department of Psychiatry, Medical Faculty, University of Cologne, Cologne, Germany.
8 Department of Neurology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
9 Ace Alzheimer Center Barcelona – Universitat Internacional de Catalunya, Barcelona, Spain
10 Amsterdam UMC, location VUmc, Department of Radiology and Nuclear Medicine, Amsterdam, The Netherlands
11 Department of Neurobiology,Care Sciences and Society, Center for Alzheimer Research,Karolinska Institutet, Stockholm, Sweden
12 Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
13 Danish Dementia Research Centre, Department of Neurology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
14 Director Neurology and Neurophysiology Section, Department Clinical and Experimental Sciences, University of Brescia
15 IMN - Institut des Maladies Neurodégénératives [Bordeaux]
16 Department of Molecular Imaging and Therapy, Austin Health, The University of Melbourne, Melbourne, VIC, Australia
17 Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
18 Latin American Institute for Brain Health (BrainLat), Universidad Adolfo Ibanez, Santiago, Chile
19 University School for Advanced Studies (IUSS), Pavia, Italy
20 Behavioral and Cognitive Neurology UNit, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte (MG), Brazil
21 Department of Cognitive Neurology, Fleni Neurological Institute, Buenos Aires, Argentina.
22 Department of Cognitive Neurosciences, Universidad de la Costa (CUC), Barranquilla, Colombia.
23 Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile
24 40. Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, Brazil
25 UNC - University of North Carolina [Chapel Hill]
26 Division of Geriatrics, University of California San Francisco
27 Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
28 Professor of Brain Health and Neurodegenerative Medicine, University of St Andrews, Scotland. UK
29 Medical Office for MIND Institute (MEA), Miami
30 Grupo de Neurociencias de Antioquia (GNA), Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
31 Department of Psychiatry, University of California San Diego Health, La Jolla, CA, USA.
32 CHU Pitié-Salpêtrière [AP-HP]
33 Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health Baltimore, MD 21224
34 Alzheimer Europe, Luxembourg
35 Department of Neurology, Mayo Clinic, Rochester, MN, USA
36 Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences
37 Dementia Research Centre, UCL Queen Square Institute of Neurology, UCL, London, UK.
38 Massachusetts General Hospital Department of Psychiatry, Boston MA
39 McLean Hospital, Belmont MA
40 Baylor College of Medicine Department of Psychiatry, Houston TX USA
41 Department of Neurosciences University of California, San Diego, La Jolla, CA, USA
42 Memory Clinic, University Hospital of Geneva, Geneva, Switzerland
2 4. Keck School of Medicine of the University of Southern California, Los Angeles, USA
3 Dementia Research Centre, Department of Neurodegenerative Disease, and the UK Dementia Research Institute, UCL Queen Square Institute of Neurology, London WC1N 3AR, UK
4 Purdue University Center for Aging and the Life Course, West Lafayette, Indiana, USA
5 Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA
6 Center for Alzheimer Research, Karolinska Institutet, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden
7 Department of Psychiatry, Medical Faculty, University of Cologne, Cologne, Germany.
8 Department of Neurology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
9 Ace Alzheimer Center Barcelona – Universitat Internacional de Catalunya, Barcelona, Spain
10 Amsterdam UMC, location VUmc, Department of Radiology and Nuclear Medicine, Amsterdam, The Netherlands
11 Department of Neurobiology,Care Sciences and Society, Center for Alzheimer Research,Karolinska Institutet, Stockholm, Sweden
12 Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
13 Danish Dementia Research Centre, Department of Neurology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
14 Director Neurology and Neurophysiology Section, Department Clinical and Experimental Sciences, University of Brescia
15 IMN - Institut des Maladies Neurodégénératives [Bordeaux]
16 Department of Molecular Imaging and Therapy, Austin Health, The University of Melbourne, Melbourne, VIC, Australia
17 Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
18 Latin American Institute for Brain Health (BrainLat), Universidad Adolfo Ibanez, Santiago, Chile
19 University School for Advanced Studies (IUSS), Pavia, Italy
20 Behavioral and Cognitive Neurology UNit, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte (MG), Brazil
21 Department of Cognitive Neurology, Fleni Neurological Institute, Buenos Aires, Argentina.
22 Department of Cognitive Neurosciences, Universidad de la Costa (CUC), Barranquilla, Colombia.
23 Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile
24 40. Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, Brazil
25 UNC - University of North Carolina [Chapel Hill]
26 Division of Geriatrics, University of California San Francisco
27 Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
28 Professor of Brain Health and Neurodegenerative Medicine, University of St Andrews, Scotland. UK
29 Medical Office for MIND Institute (MEA), Miami
30 Grupo de Neurociencias de Antioquia (GNA), Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
31 Department of Psychiatry, University of California San Diego Health, La Jolla, CA, USA.
32 CHU Pitié-Salpêtrière [AP-HP]
33 Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health Baltimore, MD 21224
34 Alzheimer Europe, Luxembourg
35 Department of Neurology, Mayo Clinic, Rochester, MN, USA
36 Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences
37 Dementia Research Centre, UCL Queen Square Institute of Neurology, UCL, London, UK.
38 Massachusetts General Hospital Department of Psychiatry, Boston MA
39 McLean Hospital, Belmont MA
40 Baylor College of Medicine Department of Psychiatry, Houston TX USA
41 Department of Neurosciences University of California, San Diego, La Jolla, CA, USA
42 Memory Clinic, University Hospital of Geneva, Geneva, Switzerland
Résumé
Importance Since 2018, a movement has emerged to define Alzheimer disease (AD) as a purely biological entity based on biomarker findings. The recent revision of the Alzheimer Association (AA) criteria for AD furthers this direction. However, concerns about a purely biological definition of AD being applied clinically, the understanding of AD by society at large, and the translation of blood-based biomarkers into clinical practice prompt these International Working Group (IWG) updated recommendations.
Objective To consider the revised AA criteria and to offer an alternative definitional view of AD as a clinical-biological construct for clinical use. The recommendations of the 2021 IWG diagnostic criteria are updated for further elaborating at-risk and presymptomatic states.
Evidence Review PubMed was searched for articles published between July 1, 2020, and March 1, 2024, using the terms “biomarker” OR “amyloid” OR “tau” OR “neurodegeneration” OR “preclinical” OR “CSF” OR “PET” OR “plasma” AND “Alzheimer’s disease.” The references of relevant articles were also searched.
Findings In the new AA diagnostic criteria, AD can be defined clinically as encompassing cognitively normal people having a core 1 AD biomarker. However, recent literature shows that the majority of biomarker-positive cognitively normal individuals will not become symptomatic along a proximate timeline. In the clinical setting, disclosing a diagnosis of AD to cognitively normal people with only core 1 AD biomarkers represents the most problematic implication of a purely biological definition of the disease.
Conclusions and Relevance The ultimate aim of the field was to foster effective AD treatments, including preventing symptoms and dementia. The approach of diagnosing AD without a clinical and biological construct would be unwarranted and potentially concerning without a clear knowledge of when or whether symptoms will ever develop. It is recommended that those who are amyloid-positive only and, more generally, most biomarker-positive cognitively normal individuals, should not be labeled as having AD. Rather, they should be considered as being at risk for AD. The expansion of presymptomatic AD is viewed as a better diagnostic construct for those with a specific pattern of biomarkers, indicating that they are proximate to the expression of symptoms in the near future.
Domaines
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