Anti-Amyloid Therapies for Alzheimer's Disease and the Amyloid Cascade Hypothesis
1Pharmacology and Toxicology Unit, Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Cembrano 4, 16148 Genoa, Italy.
Abstract:
Over the past 30 years, the majority of (pre)clinical efforts to find an effective therapy for Alzheimer's disease (AD) focused on clearing the β-amyloid peptide (Aβ) from the brain since, according to the amyloid cascade hypothesis, the peptide was (and it is still considered by many) the pathogenic determinant of this neurodegenerative disorder. However, as reviewed in this article, results from the numerous clinical trials that have tested anti-Aβ therapies to date indicate that this peptide plays a minor role in the pathogenesis of AD. Indeed, even Aducanumab and Lecanemab, the two antibodies recently approved by the FDA for AD therapy, as well as Donanemab showed limited efficacy on cognitive parameters in phase III clinical trials, despite their capability of markedly lowering Aβ brain load. Furthermore, preclinical evidence demonstrates that Aβ possesses several physiological functions, including memory formation, suggesting that AD may in part be due to a loss of function of this peptide. Finally, it is generally accepted that AD could be the result of many molecular dysfunctions, and therefore, if we keep chasing only Aβ, it means that we cannot see the forest for the trees.
Insights
Alzheimer's disease therapies targeting amyloid-beta (Aβ) have shown limited success. Research suggests Aβ may have vital functions, and focusing solely on its clearance overlooks other potential causes of Alzheimer's disease.
Area of Science:
- Neuroscience
- Pharmacology
- Pathology
Background:
- Alzheimer's disease (AD) research has predominantly focused on the amyloid cascade hypothesis, targeting β-amyloid peptide (Aβ) clearance.
- Despite decades of research and development, effective AD therapies remain elusive.
Purpose of the Study:
- To critically review the efficacy of anti-amyloid-beta therapies for Alzheimer's disease.
- To evaluate the role of Aβ in AD pathogenesis beyond its clearance.
- To explore alternative therapeutic strategies for AD.
Main Methods:
- Review of clinical trial data for anti-Aβ therapies (e.g., Aducanumab, Lecanemab, Donanemab).
- Analysis of preclinical evidence on Aβ physiological functions.
- Synthesis of current understanding of AD molecular dysfunctions.
Main Results:
- Recent FDA-approved anti-Aβ antibodies (Aducanumab, Lecanemab) and Donanemab demonstrated limited cognitive benefits in phase III trials.
- These therapies significantly reduced Aβ brain load but failed to halt disease progression effectively.
- Preclinical studies indicate Aβ has essential physiological roles, including memory formation.
Conclusions:
- The amyloid cascade hypothesis may oversimplify AD pathogenesis; Aβ's role might be less central than previously assumed.
- Focusing exclusively on Aβ clearance may be hindering the development of effective Alzheimer's disease treatments.
- A multifactorial approach considering diverse molecular dysfunctions is necessary for future AD therapeutic strategies.
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