The amyloid cascade hypothesis: are we poised for success or failure?
Open accessAbstract
The first description of Alzheimer's disease ( AD ) was made in 1907 by Alois Alzheimer ( Allgemeine Zeitschrift fur Psyciatrie und Psychisch‐Gerichtliche Medizin 64, 3, 1907), although other contemporary physicians had made similar, and rather more complete, assessments of the neuropathological changes present in the AD brain (Fischer, Monatsschr Psychiat Neurol 22, 17, 1907). Our knowledge of AD has increased dramatically and continues to accelerate. This year is 25 years after the publication of a series of papers that, in various ways, articulated the amyloid cascade hypothesis ( ACH ) for AD (Beyreuther and Masters, Brain Pathol 1, 241–251, 1991; Hardy and Allsop, Trends Pharmacol Sci 12, 383–388, 1991; Selkoe, Neuron 6, 487–498, 1991; Hardy and Higgins, Science 256, 184–185, 1992). This review will cover some familiar territory, but we shall also place the ACH into a wider context, compare it with other hypotheses for AD , explore the evolution of the hypothesis to encompass new findings, and determine, irrespective of the merits of the hypothesis itself, whether it has been useful for the research field, both in academia and in industry. Finally, we shall review how the ACH has led to a number of therapeutic approaches, all of which have, to date, failed to reach their primary efficacy end‐points in clinical trials and reflect upon what the future may hold. image We review the amyloid cascade hypothesis (ACH) and compare it with other hypotheses that have been posited to explain the initiation and progression Alzheimer's disease. We document the data that support the ACH, and also reflect upon its deficiencies. We list the recent clinical failures of amyloidocentric drugs and anticipate the results that new therapeutic approaches may deliver. This article is part of the 60th Anniversary special issue .
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Aβ presages tauopathy and neurodegeneration.
“Based on the evidence that Aβ presages tauopathy and neurodegeneration, this hypothesis argues that Aβ triggers NFT pathology leading to cognitive impairment and related pathologic sequelae.”
From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [2]
The Abstract (page unavailable) says Aβ deposition likely precedes frank neuronal and synaptic loss. It also says tau pathology precedes amyloid pathology in all cases, although amyloid may drive its later spread through the cortex. Thus, the source supports Aβ preceding neurodegeneration, but not the unqualified claim that it precedes tauopathy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredAβ triggers NFT pathology leading to cognitive impairment and related pathologic sequelae.
“this hypothesis argues that Aβ triggers NFT pathology leading to cognitive impairment and related pathologic sequelae.”
From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [2]
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- Authors
- Karran, E., & De Strooper, B.
- Affiliations
- Alzheimer’s Research UK (GB)
- VIB Center for the Biology of Disease VIB‐Leuven Leuven Belgium
- Corresponding author
- Karran, Eric
- ORCID
- Karran, Eric
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2016-06-03
- Volume
- 139
- Issue
- S2
- Pages
- 237-252
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2415660587
- Cited by
- 402
- References
- 42
- Citations by year
- 2026: 15 · 2025: 25 · 2024: 26 · 2023: 47 · 2022: 34 · 2021: 42 · 2020: 54 · 2019: 67 · 2018: 42 · 2017: 43 · 2016: 7
- FWCI
- 6.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lirias (submittedVersion)
- Funders
- Janssen Pharmaceuticals
- Topics
- Health Sciences › Medicine › Physiology › 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
- amyloid hypothesis, Alzheimer's disease, amyloid-beta, Alzheimer's disease pathogenesis, anti-amyloid therapy, clinical trial failure
- MeSH terms
- Alzheimer Disease, Amino Acid Sequence, Amyloid, Amyloidosis, Animals, Antibodies, Monoclonal, Brain, Humans, Signal Transduction, Amyloid beta-Peptides, Amyloidogenic Proteins
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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