title: Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.
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.
authors.affiliation: 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.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dubois
authors.affiliation: 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.
authors.forename: Harald
authors.initials: H
authors.lastname: Hampel
authors.affiliation: University of British Columbia, Canada.
authors.forename: Howard H
authors.initials: HH
authors.lastname: Feldman
authors.affiliation: Department of Neurology and Alzheimer Center, VU University Medical Center and Neuroscience Campus, Amsterdam, The Netherlands.
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.affiliation: University of Southern California San Diego, CA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Aisen
authors.affiliation: UMR1027, INSERM, Université Toulouse III, Toulouse University Hospital, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Andrieu
authors.affiliation: IHU-A-ICM-Institut des Neurosciences translationnelles de Paris, Paris, France.
authors.forename: Hovagim
authors.initials: H
authors.lastname: Bakardjian
authors.affiliation: INSERM U1146-CNRS UMR 7371-UPMC UM CR2, Site Pitié-Salpêtrière, Paris, France.
authors.forename: Habib
authors.initials: H
authors.lastname: Benali
authors.affiliation: 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.
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
authors.affiliation: Clinical Neurochemistry Lab, Department of Neuroscience and Physiology, University of Gothenburg, Mölndal Hospital, Sahlgrenska University Hospital, Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Federal Institute for Drugs and Medical Devices, Bonn, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Broich
authors.affiliation: AXA Research Fund & UPMC Chair, Paris, France; Laboratory of Alzheimer's Neuroimaging and Epidemiology, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Cavedo
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Crutch
authors.affiliation: INSERM U 1219, Université de Bordeaux, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dartigues
authors.affiliation: University Pierre et Marie Curie, Assistance Publique des Hôpitaux de Paris, Alzheimer-Prion Team Institut du Cerveau et de la Moelle (ICM), Paris, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Duyckaerts
authors.affiliation: 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.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Epelbaum
authors.affiliation: University Hospitals and University of Geneva, Geneva, Switzerland; IRCCS Fatebenefratelli, Brescia, Italy.
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Frisoni
authors.affiliation: McGill Center for Studies in Aging, Douglas Mental Health Research Institute, Montreal, Canada.
authors.forename: Serge
authors.initials: S
authors.lastname: Gauthier
authors.affiliation: Fondation pour la Recherche sur Alzheimer, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Remy
authors.initials: R
authors.lastname: Genthon
authors.affiliation: UMR1027, INSERM, Université Toulouse III, Toulouse University Hospital, France; Department of Clinical Neurophysiology/MEG Center, VU University Medical Center, Amsterdam.
authors.forename: Alida A
authors.initials: AA
authors.lastname: Gouw
authors.affiliation: 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.
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Habert
authors.affiliation: 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.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: 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.
authors.forename: Miia
authors.initials: M
authors.lastname: Kivipelto
authors.affiliation: AXA Research Fund & UPMC Chair, Paris, France.
authors.forename: Simone
authors.initials: S
authors.lastname: Lista
authors.affiliation: 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.
authors.forename: José-Luis
authors.initials: JL
authors.lastname: Molinuevo
authors.affiliation: Center for Alzheimer's & Neurodegenerative Disease Research, University of North Texas Health Science Center, TX, USA.
authors.forename: Sid E
authors.initials: SE
authors.lastname: O'Bryant
authors.affiliation: Memory & Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Gil D
authors.initials: GD
authors.lastname: Rabinovici
authors.affiliation: Department of Molecular Imaging, Austin Health, University of Melbourne, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Rowe
authors.affiliation: 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.
authors.forename: Stephen
authors.initials: S
authors.lastname: Salloway
authors.affiliation: Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Lon S
authors.initials: LS
authors.lastname: Schneider
authors.affiliation: 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.
authors.forename: Reisa
authors.initials: R
authors.lastname: Sperling
authors.affiliation: 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.
authors.forename: Marc
authors.initials: M
authors.lastname: Teichmann
authors.affiliation: The Alzheimer's Association Division of Medical & Scientific Relations, Chicago, USA.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Carrillo
authors.affiliation: Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cummings
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester MN, USA.
authors.forename: Cliff R
authors.initials: CR
authors.lastname: Jack
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology*; D018450:Disease Progression; D006801:Humans
keywords: Alzheimer's disease; Amyloid PET; Asymptomatic; Biomarkers; Blood biomarkers; CSF biomarkers; Diagnostic criteria; Genetics; MRI; Pathophysiology; Preclinical; Tau PET