Title: Alzheimer Disease as a Clinical-Biological Construct-An International Working Group Recommendation
Published in the journal JAMA Neurology. Here is a link to the article.
Regenstrief Institute authors: Noll Campbell, PharmD, M.S.
Abstract
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.
Authors
Bruno Dubois1,2, Nicolas Villain1,3, Lon Schneider4, Nick Fox5, Noll Campbell6,7,8, Douglas Galasko9, Miia Kivipelto10,11, Frank Jessen12,13,14, Bernard Hanseeuw15,16,17, Mercè Boada18,19, Frederik Barkhof20,21,22, Agneta Nordberg23,24, Lutz Froelich25, Gunhild Waldemar26,27, Kristian Steen Frederiksen26,27, Alessandro Padovani28,29, Vincent Planche30,31, Christopher Rowe32, Alexandre Bejanin33,34, Agustin Ibanez35,36, Stefano Cappa37,38, Paulo Caramelli39, Ricardo Nitrini40, Ricardo Allegri41,42, Andrea Slachevsky43,44,45, Leonardo Cruz de Souza39, Andrea Bozoki46, Eric Widera47,48, Kaj Blennow49,50, Craig Ritchie51,52, Marc Agronin53, Francisco Lopera54, Lisa Delano-Wood55,56,57, Stéphanie Bombois1, Richard Levy1,2, Madhav Thambisetty58, Jean Georges59, David T. Jones60,61, Helen Lavretsky62,63, Jonathan Schott64, Jennifer Gatchel65,66,67,68,69, Sandra Swantek70, Paul Newhouse71,72,73, Howard H. Feldman9,74, Giovanni B. Frisoni75,76
Affiliations
1Département de Neurologie, Groupe Hospitalier Pitié-Salpêtrière, AP-HP Sorbonne Université, Institute of Memory and Alzheimer’s Disease, Paris, France.
2Sorbonne Université, INSERM U1127, CNRS 7225, Institut du Cerveau – ICM, FrontLab, Paris, France.
3Sorbonne Université, INSERM U1127, CNRS 7225, Institut du Cerveau – ICM, Maladie d’Alzheimer, Maladies à Prions, Paris, France.
4Keck School of Medicine of the University of Southern California, Los Angeles.
5Department of Neurodegenerative Disease, Dementia Research Centre, and the United Kingdom Dementia Research Institute, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
6Purdue University College of Pharmacy, West Lafayette, Indiana.
7Purdue University Center for Aging and the Life Course, West Lafayette, Indiana.
8Indiana University Center for Aging Research, Indianapolis.
9Department of Neurosciences, University of California, San Diego, La Jolla.
10Center for Alzheimer Research, Karolinska Institutet, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden.
11Institute of Clinical Medicine/Neurology, University of Eastern Finland, Kuopio, Finland.
12Department of Psychiatry, Medical Faculty, University of Cologne, Cologne, Germany.
13German Center for Neurodegenerative Diseases, Bonn, Germany.
14Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
15Department of Neurology, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
16Institute of Neurosciences, UC Louvain, Brussels, Belgium.
17Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston.
18Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
19Networking Research Center on Neurodegenerative Diseases, Instituto de Salud Carlos III, Madrid, Spain.
20Centre for Medical Image Computing, Department of Medical Physics and Bioengineering, University College London, London, United Kingdom.
21Department of Radiology and Nuclear Medicine, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands.
22Queen Square Institute of Neurology, University College London, London, United Kingdom.
23Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden.
24Theme Inflammation and Aging, The Aging Brain, Karolinska University Hospital, Stockholm, Sweden.
25Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
26Danish Dementia Research Centre, Department of Neurology, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark.
27Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
28Neurology and Neurophysiology Section, Department Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
29Hospital Department of Continuità di Cura e Fragilità, ASST Spedali Civili di Brescia, Brescia, Italy.
30Univ. Bordeaux, CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
31Pôle de Neurosciences Cliniques, Centre Mémoire de Ressources et de Recherche, CHU de Bordeaux, Bordeaux, France.
32Department of Molecular Imaging and Therapy, Austin Health, The University of Melbourne, Melbourne, Victoria, Australia.
33Sant 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.
34Center of Biomedical Investigation Network for Neurodegenerative Diseases, Madrid, Spain.
35Latin American Institute for Brain Health (BrainLat), Universidad Adolfo Ibanez, Santiago, Chile.
36Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland.
37University School for Advanced Studies, Pavia, Italy.
38RCCS Mondino Foundation, Pavia, Italy.
39Behavioral and Cognitive Neurology Unit, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
40Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
41Department of Cognitive Neurology, Fleni Neurological Institute, Buenos Aires, Argentina.
42Department of Cognitive Neurosciences, Universidad de la Costa, Barranquilla, Colombia.
43Geroscience Center for Brain Health and Metabolism, Santiago, Chile.
44Memory and Neuropsychiatric Center Neurology Department, Hospital del Salvador and Neuropsychology and Clinical Neuroscience Laboratory, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Chile.
45Neurology and Psychiatry Department, Clínica Alemana-Universidad Desarrollo, Santiago, Chile.
46Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill.
47Division of Geriatrics, University of California, San Francisco.
48Hospice & Palliative Care, San Francisco Veterans Affairs Health Care System, San Francisco, California.
49Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
50Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
51Brain Health and Neurodegenerative Medicine, University of St Andrews, Scotland, United Kingdom.
52Scottish Brain Sciences, Edinburgh, Scotland, United Kingdom.
53Medical Office for MIND Institute, Miami, Florida.
54Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.
55Veterans Affairs San Diego Healthcare System, San Diego, California.
56Department of Psychiatry, University of California, San Diego Health, La Jolla, California.
57Center for Stress and Mental Health, VA San Diego Healthcare System, San Diego, California.
58Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
59Alzheimer Europe, Luxembourg.
60Department of Neurology, Mayo Clinic, Rochester, Minnesota.
61Department of Radiology, Mayo Clinic, Rochester, Minnesota.
62Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior.
63David Geffen School of Medicine, University of California, Los Angeles.
64Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
65Department of Psychiatry, Massachusetts General Hospital, Boston.
66McLean Hospital, Belmont, Massachusetts.
67Harvard Medical School, Boston, Massachusetts.
68Department of Psychiatry, Baylor College of Medicine, Houston, Texas.
69Michael E. DeBakey VA Medical Center, Houston, Texas.
70American Association for Geriatric Psychiatry, Brentwood, Tennessee.
71Vanderbilt University, Nashville, Tennessee.
72Center for Cognitive Medicine, Department of Psychiatry, Vanderbilt University Medical Center, Nashville, Tennessee.
73VA-TVHS Geriatric Research Education and Clinical Center, Nashville, Tennessee.
74Shiley-Marcos Alzheimer’s Disease Research Center, University of California, San Diego, La Jolla.
75Laboratory of Neuroimaging of Aging, University of Geneva, Geneva, Switzerland.
76Memory Clinic, University Hospital of Geneva, Geneva, Switzerland.
