Preclinical Alzheimer’s Disease: Definition, Natural History, and Diagnostic Criteria
Open accessAbstract
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.
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Part of the risk factors for cardiovascular disease are in common with Alzheimer's disease, including hypertension, dyslipidemia, diabetes, obesity, dietary factors, smoking, and physical activity.
“This could explain why part of the risk factors for cardiovascular disease are in common with AD, including hypertension, dyslipidemia, diabetes, obesity, dietary factors, smoking, and physical activity (Figure 1B).”
From Alzheimer's Disease: Treatment Strategies and Their Limitations. (2022) · cites this paper as [22]
Section 3.4 identifies hypertension, obesity, diabetes, physical inactivity, and smoking as AD risk factors; section 3.5 discusses diet and exercise in relation to AD risk. The paper also groups cardiovascular and lifestyle factors as modifiable AD risks, but our copy does not identify dyslipidemia as an AD risk factor, so the full list is not supported. (LLM, conf=0.87)
Experimental — accuracy not yet measuredLifestyle is an important risk factor, where intellectual, physical, and social activities, as well as diet, may help to prevent Alzheimer's disease.
“Thus, lifestyle is also an important risk factor, where intellectual, physical, and social activities, as well as diet, may help to prevent AD [1,22,100,101,102,103].”
From Alzheimer's Disease: Treatment Strategies and Their Limitations. (2022) · cites this paper as [22]
Alzheimer's disease is now regarded as a continuum rather than three distinct clinically defined entities.
“Thus, the disease is now regarded as a continuum rather than three distinct clinically defined entities [15].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [15]
IWG 2016 and the NIA research framework are aligned on the key issue that the combination of an abnormal Aβ and tau biomarker constitutes AD regardless of cognitive symptoms, and thus AD is a biologically defined entity throughout its continuum.
“While differences remain, IWG 2016 and the NIA research framework are aligned on the key issue that the combination of an abnormal Aβ and tau biomarker constitutes AD regardless of cognitive symptoms, and thus AD is a biologically defined entity throughout its continuum.”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [15]
Drug development research for Alzheimer disease has become more complicated as preclinical and prodromal Alzheimer disease populations are potentially included in current trials, as well as traditionally included populations of all clinical stages of Alzheimer disease dementia.
“Furthermore, drug development research for AD has become more complicated as preclinical and prodromal AD populations are potentially included in current trials, as well as traditionally included populations of all the clinical stages of AD dementia.38”
From Current and Future Treatments in Alzheimer Disease: An Update (2020) · cites this paper as [38]
Use of clinical trial simulators is not frequent in recent research.
“Although the use of clinical trial simulators is not frequent in recent research,38”
From Current and Future Treatments in Alzheimer Disease: An Update (2020) · cites this paper as [38]
The asymptomatic phase of AD (AsymAD) is currently considered a preclinical stage of the disease.
“This asymptomatic phase of AD (AsymAD) is currently considered a preclinical stage of the disease [27, 28].”
From Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease (2018) · cites this paper as [27]
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- Authors
- Dubois, B., Hampel, H., Feldman, H. H., Scheltens, P., Aisen, P., Andrieu, S., Bakardjian, H., Benali, H., Bertram, L., Blennow, K., Broich, K., Cavedo, E., Crutch, S., Dartigues, J., Duyckaerts, C., Epelbaum, S., Frisoni, G. B., Gauthier, S., Genthon, R., Gouw, A. A., Habert, M., Holtzman, D. M., Kivipelto, M., Lista, S., Molinuevo, J., O'Bryant, S. E., Rabinovici, G. D., Rowe, C., Salloway, S., Schneider, L. S., Sperling, R., Teichmann, M., Carrillo, M. C., Cummings, J., Jack, C. R., & Proceedings of the Meeting of the International Working Group (IWG) and the American Alzheimer's Association on “The Preclinical State of AD”; July 23, 2. W. D.
- Affiliations
- Sorbonne Université (FR)
- University of British Columbia (CA)
- Amsterdam Neuroscience (NL)
- University of Southern California (US)
- Université Toulouse III - Paul Sabatier (FR)
- Institut du Cerveau (FR)
- Centre National de la Recherche Scientifique (FR)
- Institute for Integrative and Experimental Genomics (DE)
- Sahlgrenska University Hospital (SE)
- Federal Institute for Drugs and Medical Devices (DE)
- Centro San Giovanni di Dio Fatebenefratelli (IT)
- UCL Queen Square Institute of Neurology (GB)
- Université de Bordeaux (FR)
- University of Geneva (CH)
- Douglas Mental Health University Institute (CA)
- Fondation pour la Recherche sur Alzheimer Hôpital Pitié‐Salpêtrière Paris France
- Washington University in St. Louis (US)
- Karolinska University Hospital (SE)
- AXA Research Fund (FR)
- Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona Spain
- Center for Alzheimer's & Neurodegenerative Disease Research University of North Texas Health Science Center TX USA
- University of California, San Francisco (US)
- The University of Melbourne (AU)
- Brown University (US)
- Brigham and Women's Hospital (US)
- The Alzheimer's Association Division of Medical & Scientific Relations Chicago USA
- Cleveland Clinic (US)
- Department of Radiology Mayo Clinic Rochester MN USA
- Corresponding author
- Dubois, Bruno
- ORCID
- Dubois, Bruno
- Hampel, Harald
- Feldman, Howard H.
- Scheltens, Philip
- Andrieu, Sandrine
- Bakardjian, Hovagim
- Benali, Habib
- Bertram, Lars
- Blennow, Kaj
- Broich, Karl
- Cavedo, Enrica
- Crutch, Sebastian
- Dartigues, Jean‐François
- Duyckaerts, Charles
- Epelbaum, Stéphane
- Frisoni, Giovanni B.
- Gauthier, Serge
- Gouw, Alida A.
- Habert, Marie‐Odile
- Holtzman, David M.
- Kivipelto, Miia
- Lista, Simone
- Rabinovici, Gil D.
- Rowe, Christopher
- Salloway, Stephen
- Schneider, Lon S.
- Sperling, Reisa
- Teichmann, Marc
- Cummings, Jeffrey
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2016-03
- Volume
- 12
- Issue
- 3
- Pages
- 292-323
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC6417794
- OpenAlex
- W2309442902
- Cited by
- 1,925
- References
- 298
- Citations by year
- 2026: 115 · 2025: 176 · 2024: 244 · 2023: 245 · 2022: 247 · 2021: 244 · 2020: 176 · 2019: 157 · 2018: 161 · 2017: 112 · 2016: 47
- FWCI
- 22.78
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Alzheimer s & Dementia (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- AXA Research Fund
- National Institute on Aging
- Alzheimer's Association
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Keywords
- preclinical Alzheimer's disease, Alzheimer's disease continuum
- MeSH terms
- Alzheimer Disease, Animals, Brain, Humans, Disease Progression
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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