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The probabilistic model of Alzheimer disease: the amyloid hypothesis revised
Open accessAbstract
The current conceptualization of Alzheimer disease (AD) is driven by the amyloid hypothesis, in which a deterministic chain of events leads from amyloid deposition and then tau deposition to neurodegeneration and progressive cognitive impairment. This model fits autosomal dominant AD but is less applicable to sporadic AD. Owing to emerging information regarding the complex biology of AD and the challenges of developing amyloid-targeting drugs, the amyloid hypothesis needs to be reconsidered. Here we propose a probabilistic model of AD in which three variants of AD (autosomal dominant AD, APOE ε4-related sporadic AD and APOE ε4-unrelated sporadic AD) feature decreasing penetrance and decreasing weight of the amyloid pathophysiological cascade, and increasing weight of stochastic factors (environmental exposures and lower-risk genes). Together, these variants account for a large share of the neuropathological and clinical variability observed in people with AD. The implementation of this model in research might lead to a better understanding of disease pathophysiology, a revision of the current clinical taxonomy and accelerated development of strategies to prevent and treat AD.
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“Of note, the amyloid cascade hypothesis remains controversial. This theory faces challenges in explaining the diverse pathological features, shows a weak correlation between Aβ and cognitive decline, and has failed to demonstrate efficacy in numerous clinical drugs to target Aβ.118,144–147”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [145]
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Metadata
- Authors
- Frisoni, G. B., Altomare, D., Thal, D. R., Ribaldi, F., van der Kant, R., Ossenkoppele, R., Blennow, K., Cummings, J., van Duijn, C., Nilsson, P. M., Dietrich, P.-Y., Scheltens, P., & Dubois, B.
- Affiliations
- University of Geneva (CH)
- Universitair Ziekenhuis Leuven (BE)
- Lund University (SE)
- Sahlgrenska University Hospital (SE)
- University of Nevada, Las Vegas (US)
- University Hospital of Geneva (CH)
- Amsterdam Neuroscience (NL)
- Inserm (FR)
- Corresponding author
- Frisoni, Giovanni B.
- ORCID
- Venue
- Nature Reviews Neuroscience
- Published
- 2021-11-23
- Volume
- 23
- Issue
- 1
- Pages
- 53-66
- ISSN
- 1471-003X (ISSN-L)
- 1471-0048
- PMC
- PMC8840505
- OpenAlex
- W3215063364
- Cited by
- 513
- References
- 215
- Citations by year
- 2026: 81 · 2025: 108 · 2024: 107 · 2023: 134 · 2022: 81 · 2021: 2
- FWCI
- 10.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature reviews. Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion)
- VU Research Portal (submittedVersion, other-oa)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- National Science Foundation
- Pfizer (P20GM109025)
- AstraZeneca
- Biogen (P20GM109025)
- Teva Pharmaceutical Industries
- Alnylam Pharmaceuticals
- Velux Stiftung
- European Federation of Pharmaceutical Industries and Associations (115736, 115952)
- TauRx Pharmaceuticals
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (115952, 182772)
- Fonds Wetenschappelijk Onderzoek (G0F8516N)
- Eisai (P20GM109025)
- Hjärnfonden (FO2017‑0243, FO2017, ALFGBG-715986)
- Vetenskapsrådet (2017-00915, (#ALFGBG-715986, FO2017-0243)
- Vifor Pharma
- Alzheimer Nederland
- Vlaamse regering
- Merz Pharmaceuticals
- H. Lundbeck A/S (P20GM109025)
- IXICO
- Fondation Segré
- Genentech (P20GM109025)
- Novartis Pharma
- Avid Radiopharmaceuticals
- National Institute on Aging (R01AG053798, P20AG068053, P30AG072980)
- National Institute of General Medical Sciences (P20GM109025)
- National Institute of Neurological Disorders and Stroke (U01NS093334)
- Janssen Pharmaceuticals
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid hypothesis, probabilistic models, autosomal dominant Alzheimer's disease, sporadic Alzheimer's disease, APOE ε4, disease penetrance, stochastic factors, environmental exposure, risk genes, amyloid deposition, tau deposition, neurodegeneration
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Humans, Models, Statistical, Amyloid beta-Peptides, tau Proteins, Amyloid Neuropathies
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