The DOI matches its Crossref record; 217 of the 218 references it cites were found in a registry or an index.
Inconsistencies and Controversies Surrounding the Amyloid Hypothesis of Alzheimer's Disease
Open accessAbstract
The amyloid hypothesis has driven drug development strategies for Alzheimer's disease for over 20 years. We review why accumulation of amyloid-beta (Aβ) oligomers is generally considered causal for synaptic loss and neurodegeneration in AD. We elaborate on and update arguments for and against the amyloid hypothesis with new data and interpretations, and consider why the amyloid hypothesis may be failing therapeutically. We note several unresolved issues in the field including the presence of Aβ deposition in cognitively normal individuals, the weak correlation between plaque load and cognition, questions regarding the biochemical nature, presence and role of Aβ oligomeric assemblies in vivo, the bias of pre-clinical AD models toward the amyloid hypothesis and the poorly explained pathological heterogeneity and comorbidities associated with AD. We also illustrate how extensive data cited in support of the amyloid hypothesis, including genetic links to disease, can be interpreted independently of a role for Aβ in AD. We conclude it is essential to expand our view of pathogenesis beyond Aβ and tau pathology and suggest several future directions for AD research, which we argue will be critical to understanding AD pathogenesis.
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“along with the lack of correlation between plaque load and cognitive decline in AD patients3”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [3]
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Items 201–217 of 217
Genetic and Environmental Modifiers of Alzheimers Disease Phenotypes in the Mouse
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A Patient with Posterior Cortical Atrophy Possesses a Novel Mutation in the Presenilin 1 Gene
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The amyloid cascade hypothesis has misled the pharmaceutical industry
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An overlooked neurotoxic species in Alzheimer's disease
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Uncertain Progress on the Fuzzy Boundaries of Alzheimer's Disease: Reading Between the Guidelines
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Can tauopathy shake the amyloid cascade hypothesis?
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Old mice require new experimental tricks to study aging process
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Amyloid beta: Functional protein or biological junk?
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Flagged first, then by citations
1 of the 218 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- Roche IU: Roche announces phase II clinical results of crenezumab in Alzheimer’s disease. 2014.
- Zakaib GW: Anti-Amyloid Therapies Combine Forces to Knock Out Plaques. 2014.
Cited by
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Inflammation as a central mechanism in Alzheimer's disease
Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A. M., & Lamb, B. T. (2018) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.06.014 · Cited by 2,253
“As stated previously, patients may exhibit Ab plaque pathology for up to or greater than a decade before any overt diagnosis of AD [35,36].”
BackgroundA critical appraisal of amyloid-β-targeting therapies for Alzheimer disease
Panza, F., Lozupone, M., Logroscino, G., & Imbimbo, B. P. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-018-0116-6 · Cited by 965
The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade
Cline, E. N., Bicca, M. A., Viola, K. L., & Klein, W. L. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179941 · Cited by 870
Yuan, P., Condello, C., Keene, C. D., Wang, Y., Bird, T. D., Paul, S. M., Luo, W., Colonna, M., Baddeley, D., & Grutzendler, J. (2016) · Neuron · doi:10.1016/j.neuron.2016.05.003 · Cited by 817
Molecular genetics of early-onset Alzheimer’s disease revisited
Cacace, R., Sleegers, K., & Van Broeckhoven, C. (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.01.012 · Cited by 617
Metadata
- Authors
- Morris, G. P., Clark, I. A., & Vissel, B.
- Affiliations
- Garvan Institute of Medical Research (AU)
- Australian National University (AU)
- Corresponding author
- Vissel, Bryce
- Venue
- Acta Neuropathologica Communications
- Published
- 2014-09-18
- Volume
- 2
- Issue
- 1
- Pages
- 135-135
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC4207354
- OpenAlex
- W2148020885
- Cited by
- 522
- References
- 218
- Citations by year
- 2026: 13 · 2025: 44 · 2024: 47 · 2023: 47 · 2022: 42 · 2021: 41 · 2020: 48 · 2019: 59 · 2018: 63 · 2017: 46 · 2016: 49 · 2015: 22 · 2014: 1
- FWCI
- 26.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ANU Open Research (Australian National University) (submittedVersion, cc-by)
- UTS ePRESS (University of Technology Sydney) (submittedVersion)
- 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
- amyloid hypothesis, Alzheimer's disease, amyloid-beta oligomers, amyloid plaques, synaptic loss, neurodegeneration, cognitively normal individuals, genetic risk factors, tau pathology, pathological heterogeneity, comorbidities, Alzheimer's disease pathogenesis
- MeSH terms
- Alzheimer Disease, Humans, Synapses, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Plaque, Amyloid
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