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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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.
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.
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- Alzheimer disease
(AD). The co-occurrence of brain Aβ and tau pathology. AD dementia is the final stage of AD, in which cognitive impairment and loss of daily function are also present.
In the brain, a 37–49-amino-acid polypeptide (amyloid-β (Aβ)) produced by the metabolism of the synaptic membrane protein amyloid precursor protein (APP). The amyloid fibrillar form is made mainly of the 42-amino-acid variant (Aβ42) and is the primary component of amyloid plaques found in the brains of individuals with Alzheimer disease. Soluble Aβ42 can be found in plasma and the cerebrospinal fluid and can give rise to soluble oligomers, thought to be the toxic form of Aβ.
- Braak stage
Braak stage denotes the degree of tau pathology in Alzheimer disease and assumes progressive spread of such pathology from the transentorhinal region of the brain. Braak stages I and II denote neurofibrillary tangle involvement confined mainly to the transentorhinal region, stages III and IV when there is also involvement of limbic regions such as the hippocampus, and stages V and VI when there is extensive neocortical involvement.
- Mild cognitive impairment
(MCI). A syndrome featuring cognitive impairment and no loss of daily function; Alzheimer disease is the underlying pathology in 60–80% of MCI cases. In these cases, the condition is also called prodromal Alzheimer disease or MCI due to Alzheimer disease.
Progressive loss of the structure or function of neurons, which may ultimately involve cell death. The earliest detectable event is thought to be synaptic loss, followed by neuronal loss. Neurodegeneration can be detected in vivo with volumetric MRI and positron emission tomography with 18F-labelled deoxyglucose.
A protein whose primary role is in maintaining the stability of microtubules in axons. In the course of Alzheimer disease, tau becomes hyperphosphorylated, leading to axonal and synaptic dysfunction and aggregation of tau into intracellular neurofibrillary tangles.
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Frisoni, G.B., Altomare, D., Thal, D.R. et al. The probabilistic model of Alzheimer disease: the amyloid hypothesis revised. Nat Rev Neurosci 23, 53–66 (2022). https://doi.org/10.1038/s41583-021-00533-w