Anti-Amyloid Therapies for Alzheimer’s Disease and the Amyloid Cascade Hypothesis
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 pathogeni...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/19/14499 |
| _version_ | 1797575809163067392 |
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| author | Ernesto Fedele |
| author_facet | Ernesto Fedele |
| author_sort | Ernesto Fedele |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T21:43:36Z |
| format | Article |
| id | doaj.art-55736c9a5a7543239ff2c185c1e3da90 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T21:43:36Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-55736c9a5a7543239ff2c185c1e3da902023-11-19T14:27:32ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-09-0124191449910.3390/ijms241914499Anti-Amyloid Therapies for Alzheimer’s Disease and the Amyloid Cascade HypothesisErnesto Fedele0Pharmacology and Toxicology Unit, Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Cembrano 4, 16148 Genoa, ItalyOver 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.https://www.mdpi.com/1422-0067/24/19/14499Alzheimer’s diseaseAβ antibodiesamyloid cascade hypothesisclinical trials |
| spellingShingle | Ernesto Fedele Anti-Amyloid Therapies for Alzheimer’s Disease and the Amyloid Cascade Hypothesis International Journal of Molecular Sciences Alzheimer’s disease Aβ antibodies amyloid cascade hypothesis clinical trials |
| title | Anti-Amyloid Therapies for Alzheimer’s Disease and the Amyloid Cascade Hypothesis |
| title_full | Anti-Amyloid Therapies for Alzheimer’s Disease and the Amyloid Cascade Hypothesis |
| title_fullStr | Anti-Amyloid Therapies for Alzheimer’s Disease and the Amyloid Cascade Hypothesis |
| title_full_unstemmed | Anti-Amyloid Therapies for Alzheimer’s Disease and the Amyloid Cascade Hypothesis |
| title_short | Anti-Amyloid Therapies for Alzheimer’s Disease and the Amyloid Cascade Hypothesis |
| title_sort | anti amyloid therapies for alzheimer s disease and the amyloid cascade hypothesis |
| topic | Alzheimer’s disease Aβ antibodies amyloid cascade hypothesis clinical trials |
| url | https://www.mdpi.com/1422-0067/24/19/14499 |
| work_keys_str_mv | AT ernestofedele antiamyloidtherapiesforalzheimersdiseaseandtheamyloidcascadehypothesis |