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The Amyloid Cascade Hypothesis in Alzheimer’s Disease: It’s Time to Change Our Mind
Open accessAbstract
Since its discovery in 1984, the beta amyloid peptide has treaded the boards of neurosciences as the star molecule in Alzheimer's disease pathogenesis. In the last decade, however, this vision has been challenged by evidence-based medicine showing the almost complete failure of clinical trials that experimented anti-amyloid therapies with great hopes. Moreover, data have accumulated which clearly indicate that this small peptide plays a key role in the physiological processes of memory formation. In the present review, we will discuss the different aspects of the amyloid cascade hypothesis, highlighting its pros and cons, and we will analyse the results of the therapeutic approaches attempted to date that should change the direction of Alzheimer's disease research in the future.
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“Therefore, more integrative hypotheses have suggested that inflammation, excitatory‐inhibitory imbalance, or vascular impairment is involved in the series of initial reactions that eventually become chronic and result in irreversible brain dyshomeostasis, neurodegeneration, and AD [42, 66, 69].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: APOE3 Christchurch homozygote glioprotection (2023) · cites this paper as [69]
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“Under healthy conditions, soluble monomeric Aβ contributes to synaptic regulation, neuronal signaling, and neuroprotection through modulation of calcium homeostasis, metal ion binding, and antimicrobial defense [41–43].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [42]
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Metadata
- Authors
- Ricciarelli, R., & Fedele, E.
- Affiliations
- University of Genoa (IT)
- Corresponding author
- Ricciarelli, Roberta
- Fedele, Ernesto
- Venue
- Current Neuropharmacology
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2017-07-31
- Volume
- 15
- Issue
- 6
- Pages
- 926-935
- ISSN
- 1570-159X (ISSN-L)
- PMC
- PMC5652035
- OpenAlex
- W2581177196
- Cited by
- 380
- References
- 111
- Citations by year
- 2026: 22 · 2025: 30 · 2024: 49 · 2023: 60 · 2022: 53 · 2021: 58 · 2020: 51 · 2019: 33 · 2018: 13 · 2017: 11
- FWCI
- 21.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc
- Locations
- Current Neuropharmacology (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (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, anti-amyloid therapy, clinical trial failure, memory formation, Alzheimer's disease pathogenesis
- MeSH terms
- Alzheimer Disease, Animals, Brain, Humans, Amyloid beta-Peptides
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