The probabilistic model of Alzheimer disease: the amyloid hypothesis revised

Giovanni B. Frisoni*, Daniele Altomare, Dietmar Rudolf Thal, Federica Ribaldi, Rik van der Kant, Rik Ossenkoppele, Kaj Blennow, Jeffrey Cummings, Cornelia van Duijn, Peter M. Nilsson, Pierre Yves Dietrich, Philip Scheltens, Bruno Dubois

*Corresponding author for this work

Research output: Contribution to journalReview articleAcademicpeer-review

146 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)53-66
Number of pages14
JournalNature Reviews Neuroscience
Issue number1
Publication statusPublished - Jan 2022

Bibliographical note

Funding Information:
G.B.F. has received grants from Avid Radiopharmaceuticals, Biogen, GE International, Guerbert, IXICO, Merz Pharma, Nestlé, Novartis, Eisai, Piramal, Roche, Siemens, Teva Pharmaceutical Industries and Vifor Pharma. He has received personal fees from AstraZeneca, Avid Radiopharmaceuticals, Biogen, Roche, Diadem, Neurodiem, Elan Pharmaceuticals, GE International, Lundbeck, Pfizer and TauRx Therapeutics. D.R.T. has received speaker honoraria from Novartis Pharma Basel (Switzerland) and Biogen (USA), has received travel reimbursement from GE Healthcare (UK), and UCB (Belgium) and has collaborated with GE Healthcare (UK), Novartis Pharma Basel (Switzerland), Probiodrug (Germany) and Janssen Pharmaceuticals (Belgium). K.B. has served as a consultant, on advisory boards or on data monitoring committees for Abcam, Axon, Biogen, Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is part of the GU Ventures incubator programme. J.C. has acted as a consultant for Acadia, Actinogen, Alkahest, Alzheon, Annovis, Avanir, Axsome, Biogen, Cassava, Cerecin, Cerevel, Cortexyme, Cytox, EIP Pharma, Eisai, Foresight, GemVax, Genentech, Green Valley, Grifols, Karuna, Merck, Novo Nordisk, Otsuka, Resverlogix, Roche, Samumed, Samus, Signant Health, Suven and United Neuroscience. J.C. also has stock options in ADAMAS, AnnovisBio, MedAvante and BiOasis, and owns the copyright of the Neuropsychiatric Inventory. P.S. has received consultancy fees (paid to Amsterdam UMC) from AC Immune, Brainstorm Cell, EIP, ImmunoBrain Checkpoint, Genentech, Novartis, and Novo Noridisk. He is a principal investigator on studies with AC Immune, FUJIFILM Toyama, UCB, and Vivoryon. He is a part-time employee of Life Sciences Partners Amsterdam. B.D. has received research funding (paid to the institution) from Merck-Avenir Foundation and Roche and consultancy fees from Biogen, Neurodiem, Green Valley, Cytox and Brainstorm. He is a principal investigator on clinical trials with Eisai, Genentech, Novartis, Biogen and Roche. D.A., F.R., R.v.d.K., R.O., C.v.D., P.M.N. and P.-Y.D. declare no competing interests.

Funding Information:
This Perspective was the result of a workshop funded by the Swiss National Science Foundation entitled “How many roads lead to Rome? Insights in Alzheimer disease pathophysiology to lead future drug development” (grant number IZSEZ0_192840). G.B.F. received funding from the following sources: European Prevention of Alzheimer’s Dementia - EPAD (grant agreement number 115736) and Amyloid Imaging to Prevent Alzheimer’s Disease - AMYPED (grant agreement number 115952) funded by the EU–EFPIA Innovative Medicines Initiatives 2 Joint Undertaking; the Swiss National Science Foundation (“Brain connectivity and metacognition in persons with subjective cognitive decline (COSCODE): correlation with clinical features and in vivo neuropathology” (grant number 320030_182772)); Association Suisse pour la Recherche sur la Maladie d’Alzheimer, Geneva; Fondation Segré, Geneva; I. Pictet, Geneva; Fondazione Agusta, Lugano; Fondation Chmielewski, Geneva; and the VELUX Foundation. D.R.T. received funding from Fonds Wetenschappelijk Onderzoek Vlaanderen (FWO-G0F8516N Odysseus). R.v.d.K. was supported by an Alzheimer Nederland pilot grant (WE.03-2017-08) and a grant from the Selfridges Group Foundation (NR170059). K.B. is supported by the Swedish Research Council (2017-00915), the Swedish Alzheimer Foundation (AF-742881), Hjärnfonden, Sweden (FO2017-0243), and the Swedish state under an agreement between the Swedish government and the county councils, the ALF agreement (ALFGBG-715986). J.C. is supported by Keep Memory Alive, NIGMS grant P20GM109025, NINDS grant U01NS093334 and NIA grant R01AG053798.

Publisher Copyright:
© 2021, Springer Nature Limited.


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