Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria

Bruno Dubois¹, Harald Hampel², Howard H Feldman³, Philip Scheltens⁴, Paul Aisen⁵, Sandrine Andrieu⁶, Hovagim Bakardjian⁷, Habib Benali⁸, Lars Bertram⁹, Kaj Blennow¹⁰, Karl Broich¹¹, Enrica Cavedo¹², Sebastian Crutch¹³, Jean-François Dartigues¹⁴, Charles Duyckaerts¹⁵, Stéphane Epelbaum¹⁶, Giovanni B Frisoni¹⁷, Serge Gauthier¹⁸, Remy Genthon¹⁹, Alida A Gouw²⁰, Marie-Odile Habert²¹, David M Holtzman²², Miia Kivipelto²³, Simone Lista²⁴, José-Luis Molinuevo²⁵, Sid E O'Bryant²⁶, Gil D Rabinovici²⁷, Christopher Rowe²⁸, Stephen Salloway²⁹, Lon S Schneider³⁰, Reisa Sperling³¹, Marc Teichmann¹⁶, Maria C Carrillo³², Jeffrey Cummings³³, Cliff R Jack Jr³⁴; Proceedings of the Meeting of the International Working Group (IWG) and the American Alzheimer's Association on “The Preclinical State of AD”; July 23, 2015; Washington DC, USA

Affiliations

¹ Institute of Memory and Alzheimer's Disease (IM2A) and Brain and Spine Institute (ICM) UMR S 1127 Frontlab, Department of Neurology, AP_HP, Pitié-Salpêtrière University Hospital, Sorbonne Universities, Pierre et Marie Curie University, Paris 06, Paris, France. Electronic address: bruno.dubois@aphp.fr.
² Institute of Memory and Alzheimer's Disease (IM2A) and Brain and Spine Institute (ICM) UMR S 1127 Frontlab, Department of Neurology, AP_HP, Pitié-Salpêtrière University Hospital, Sorbonne Universities, Pierre et Marie Curie University, Paris 06, Paris, France; AXA Research Fund & UPMC Chair, Paris, France.
³ University of British Columbia, Canada.
⁴ Department of Neurology and Alzheimer Center, VU University Medical Center and Neuroscience Campus, Amsterdam, The Netherlands.
⁵ University of Southern California San Diego, CA, USA.
⁶ UMR1027, INSERM, Université Toulouse III, Toulouse University Hospital, France.
⁷ IHU-A-ICM-Institut des Neurosciences translationnelles de Paris, Paris, France.
⁸ INSERM U1146-CNRS UMR 7371-UPMC UM CR2, Site Pitié-Salpêtrière, Paris, France.
⁹ Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany; School of Public Health, Faculty of Medicine, Imperial College London, London, UK.
¹⁰ Clinical Neurochemistry Lab, Department of Neuroscience and Physiology, University of Gothenburg, Mölndal Hospital, Sahlgrenska University Hospital, Mölndal, Sweden.
¹¹ Federal Institute for Drugs and Medical Devices, Bonn, Germany.
¹² AXA Research Fund & UPMC Chair, Paris, France; Laboratory of Alzheimer's Neuroimaging and Epidemiology, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
¹³ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK.
¹⁴ INSERM U 1219, Université de Bordeaux, France.
¹⁵ University Pierre et Marie Curie, Assistance Publique des Hôpitaux de Paris, Alzheimer-Prion Team Institut du Cerveau et de la Moelle (ICM), Paris, France.
¹⁶ Institute of Memory and Alzheimer's Disease (IM2A) and Brain and Spine Institute (ICM) UMR S 1127 Frontlab, Department of Neurology, AP_HP, Pitié-Salpêtrière University Hospital, Sorbonne Universities, Pierre et Marie Curie University, Paris 06, Paris, France.
¹⁷ University Hospitals and University of Geneva, Geneva, Switzerland; IRCCS Fatebenefratelli, Brescia, Italy.
¹⁸ McGill Center for Studies in Aging, Douglas Mental Health Research Institute, Montreal, Canada.
¹⁹ Fondation pour la Recherche sur Alzheimer, Hôpital Pitié-Salpêtrière, Paris, France.
²⁰ UMR1027, INSERM, Université Toulouse III, Toulouse University Hospital, France; Department of Clinical Neurophysiology/MEG Center, VU University Medical Center, Amsterdam.
²¹ Sorbonne Universités, UPMC Univ Paris 06, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, Paris, France; AP-HP, Hôpital Pitié-Salpêtrière, Département de Médecine Nucléaire, Paris, France.
²² Department of Neurology, Washington University, Hope Center for Neurological Disorders, St. Louis, MO, USA; Department of Neurology, Washington University, Knight Alzheimer's Disease Research Center, St. Louis, MO, USA.
²³ Center for Alzheimer Research, Karolinska Institutet, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden; Institute of Clinical Medicine/ Neurology, University of Eastern Finland, Kuopio, Finland.
²⁴ AXA Research Fund & UPMC Chair, Paris, France.
²⁵ Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain.
²⁶ Center for Alzheimer's & Neurodegenerative Disease Research, University of North Texas Health Science Center, TX, USA.
²⁷ Memory & Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
²⁸ Department of Molecular Imaging, Austin Health, University of Melbourne, Australia.
²⁹ Memory and Aging Program, Butler Hospital, Alpert Medical School of Brown University, USA; Department of Neurology, Alpert Medical School of Brown University, USA; Department of Psychiatry, Alpert Medical School of Brown University, USA.
³⁰ Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
³¹ Harvard Medical School, Memory Disorders Unit, Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Boston, USA; Harvard Medical School, Memory Disorders Unit, Center for Alzheimer Research and Treatment, Massachusetts General Hospital, Boston, USA.
³² The Alzheimer's Association Division of Medical & Scientific Relations, Chicago, USA.
³³ Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.
³⁴ Department of Radiology, Mayo Clinic, Rochester MN, USA.

PMID: 27012484
PMCID: PMC6417794
DOI: 10.1016/j.jalz.2016.02.002

Review

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria

Bruno Dubois et al. Alzheimers Dement. 2016 Mar.

. 2016 Mar;12(3):292-323.

doi: 10.1016/j.jalz.2016.02.002.

Authors

Affiliations

¹ Institute of Memory and Alzheimer's Disease (IM2A) and Brain and Spine Institute (ICM) UMR S 1127 Frontlab, Department of Neurology, AP_HP, Pitié-Salpêtrière University Hospital, Sorbonne Universities, Pierre et Marie Curie University, Paris 06, Paris, France. Electronic address: bruno.dubois@aphp.fr.
² Institute of Memory and Alzheimer's Disease (IM2A) and Brain and Spine Institute (ICM) UMR S 1127 Frontlab, Department of Neurology, AP_HP, Pitié-Salpêtrière University Hospital, Sorbonne Universities, Pierre et Marie Curie University, Paris 06, Paris, France; AXA Research Fund & UPMC Chair, Paris, France.
³ University of British Columbia, Canada.
⁴ Department of Neurology and Alzheimer Center, VU University Medical Center and Neuroscience Campus, Amsterdam, The Netherlands.
⁵ University of Southern California San Diego, CA, USA.
⁶ UMR1027, INSERM, Université Toulouse III, Toulouse University Hospital, France.
⁷ IHU-A-ICM-Institut des Neurosciences translationnelles de Paris, Paris, France.
⁸ INSERM U1146-CNRS UMR 7371-UPMC UM CR2, Site Pitié-Salpêtrière, Paris, France.
⁹ Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany; School of Public Health, Faculty of Medicine, Imperial College London, London, UK.
¹⁰ Clinical Neurochemistry Lab, Department of Neuroscience and Physiology, University of Gothenburg, Mölndal Hospital, Sahlgrenska University Hospital, Mölndal, Sweden.
¹¹ Federal Institute for Drugs and Medical Devices, Bonn, Germany.
¹² AXA Research Fund & UPMC Chair, Paris, France; Laboratory of Alzheimer's Neuroimaging and Epidemiology, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
¹³ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK.
¹⁴ INSERM U 1219, Université de Bordeaux, France.
¹⁵ University Pierre et Marie Curie, Assistance Publique des Hôpitaux de Paris, Alzheimer-Prion Team Institut du Cerveau et de la Moelle (ICM), Paris, France.
¹⁶ Institute of Memory and Alzheimer's Disease (IM2A) and Brain and Spine Institute (ICM) UMR S 1127 Frontlab, Department of Neurology, AP_HP, Pitié-Salpêtrière University Hospital, Sorbonne Universities, Pierre et Marie Curie University, Paris 06, Paris, France.
¹⁷ University Hospitals and University of Geneva, Geneva, Switzerland; IRCCS Fatebenefratelli, Brescia, Italy.
¹⁸ McGill Center for Studies in Aging, Douglas Mental Health Research Institute, Montreal, Canada.
¹⁹ Fondation pour la Recherche sur Alzheimer, Hôpital Pitié-Salpêtrière, Paris, France.
²⁰ UMR1027, INSERM, Université Toulouse III, Toulouse University Hospital, France; Department of Clinical Neurophysiology/MEG Center, VU University Medical Center, Amsterdam.
²¹ Sorbonne Universités, UPMC Univ Paris 06, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, Paris, France; AP-HP, Hôpital Pitié-Salpêtrière, Département de Médecine Nucléaire, Paris, France.
²² Department of Neurology, Washington University, Hope Center for Neurological Disorders, St. Louis, MO, USA; Department of Neurology, Washington University, Knight Alzheimer's Disease Research Center, St. Louis, MO, USA.
²³ Center for Alzheimer Research, Karolinska Institutet, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden; Institute of Clinical Medicine/ Neurology, University of Eastern Finland, Kuopio, Finland.
²⁴ AXA Research Fund & UPMC Chair, Paris, France.
²⁵ Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain.
²⁶ Center for Alzheimer's & Neurodegenerative Disease Research, University of North Texas Health Science Center, TX, USA.
²⁷ Memory & Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
²⁸ Department of Molecular Imaging, Austin Health, University of Melbourne, Australia.
²⁹ Memory and Aging Program, Butler Hospital, Alpert Medical School of Brown University, USA; Department of Neurology, Alpert Medical School of Brown University, USA; Department of Psychiatry, Alpert Medical School of Brown University, USA.
³⁰ Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
³¹ Harvard Medical School, Memory Disorders Unit, Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Boston, USA; Harvard Medical School, Memory Disorders Unit, Center for Alzheimer Research and Treatment, Massachusetts General Hospital, Boston, USA.
³² The Alzheimer's Association Division of Medical & Scientific Relations, Chicago, USA.
³³ Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.
³⁴ Department of Radiology, Mayo Clinic, Rochester MN, USA.

PMID: 27012484
PMCID: PMC6417794
DOI: 10.1016/j.jalz.2016.02.002

Abstract

During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.

Keywords: Alzheimer's disease; Amyloid PET; Asymptomatic; Biomarkers; Blood biomarkers; CSF biomarkers; Diagnostic criteria; Genetics; MRI; Pathophysiology; Preclinical; Tau PET.

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Figures

**Fig. 1.**
Proposal for a unified lexicon for preclinical AD. Abbreviation: AD, Alzheimer’s disease.

**Fig. 2.**
The risk of clinical AD–hypothetical model. Abbreviation: AD, Alzheimer’s disease; BM, pathophysiological biomarkers.

See this image and copyright information in PMC

Comment in

Toward a consensus recommendation for defining the asymptomatic-preclinical phases of putative Alzheimer's disease?
Khachaturian ZS, Mesulam MM, Mohs RC, Khachaturian AS. Khachaturian ZS, et al. Alzheimers Dement. 2016 Mar;12(3):213-5. doi: 10.1016/j.jalz.2016.02.003. Alzheimers Dement. 2016. PMID: 27012483 No abstract available.

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Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria

Affiliations

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria

Authors

Affiliations

Abstract

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Grants and funding

LinkOut - more resources

Full Text Sources

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Medical

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