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 beta-amyloid peptide (A beta) 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-A beta 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 A beta brain load. Furthermore, preclinical evidence demonstrates that A beta 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 A beta, it means that we cannot see the forest for the trees.

Automated summary

In the past 30 years, most efforts to treat Alzheimer's disease (AD) have focused on clearing the beta-amyloid peptide (A beta) from the brain. However, clinical trial results suggest that A beta plays a minor role in the pathogenesis of AD. Additionally, A beta has been found to have various physiological functions, including memory formation, indicating that the loss of A beta function may contribute to AD. It is believed that AD could be the result of multiple molecular dysfunctions, and therefore, solely targeting A beta may overlook other important factors.