Alzheimer’s Disease: Causes and Treatment

: 黃俊淵 / 聚和國際 R&D 實習生

攝影師:cottonbro: https://www.pexels.com/zh-tw/photo/3952241/

 

What is Alzheimer's disease

Alzheimer's disease (AD), commonly known as Senile Dementia, which is named because it usually occurs at old age, and the most widely known early symptom is short-term memory loss, which follows with behavioral problems such as language disorders. The cause of AD is still unknown, but it is generally considered a neurodegenerative disease [1] and is associated with Tau proteins and Aβ plaques. The current response to AD is primarily for temporary improvement in symptoms (Acetylcholinesterase inhibitor and NMDA (N-methyl-D-aspartate antagonist)), so far, there is no real drug that improves Alzheimer's disease.
 

Pathogenesis of Alzheimer's disease

The current mainstream hypothesis on pathogenesis of AD is the toxicity caused by the abnormal extracellular deposition of amyloid beta (Aβ) peptides [2], and the hypothesis is also supported by Down syndrome researchers [3]. Based on this hypothesis, Biogen Inc., an American multinational biotechnology company based in Cambridge, Massachusetts, has developed a drug called Aducanumab (Aduhelm), which acts on the stages after amyloid beta (Aβ) oligomerization, thereby reducing Aβ plaques deposition (Figure 1). Aducanumab is currently considered to be an agent with a high probability of effectively blocking the AD process.
 

Aducanumab and the controversy

The FDA showed at an Expert Advisory Group meeting in November 2020 that Biogen drug testing was terminated prematurely due to lack of efficacy and that there was insufficient evidence to support the efficacy of Aducanumab [5]. Biogen's subsequent retrospective analysis reported positive results and severe side effects on multiple participants in the trial. Based on the above-mentioned doubts, the FDA doubts the efficacy of this drug and the credibility of the test [6].

Despite the majority of the advisory panel's disapproval, the FDA issued a mid-term statement on June 7, 2021, stating that it would expedite the review of the drug. However, the Phase 4 clinical trial of Aducanumab still needs to be conducted to provide evidence of clinical efficacy for alternative endpoints [7]. The decision caused dissatisfaction among many FDA advisory panel members, who also resigned in protest. In this regard, Biogen said that if the course of AD could be delayed, the global burden of disease will drop significantly. This is justified by the FDA's accelerated review attempt to demonstrate surrogate endpoints, given the failed clinical trials in AD studies. So far, the efficacy and approval of the drug are still inconclusive. Hopefully a desired result will come out in the near future.
 

(Figure 1) Aducanumab acts on processes of Aβ oligomerization to reduce plaque production [4].
 

References
[1] Bure, A. & Iliffe, S. Alzhimer’s disease. BMJ, 2009; 338: 467-471. doi:10.1136/bmj.b158
[2] Reiss, Allison B., Arain, Hirra A., Stecker, Mark M., Siegart, Nicolle M. and Kasselman, Lora J. "Amyloid toxicity in Alzheimer’s disease" Reviews in the Neurosciences, 2018; 29(6): 613-627. doi: 10.1515/revneuro-2017-0063
[3] Lott IT, Head E. Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol. 2019 Mar; 15(3): 135-147. doi: 10.1038/s41582-018-0132-6
[4] Esang M, Gupta M. Aducanumab as a Novel Treatment for Alzheimer’s Disease: A Decade of Hope, Controversies, and the Future. 2021 Aug; Cureus 13(8): e17591. doi:10.7759/cureus.17591
[5] FDA approval of new Alzheimer’s drug Aduhelm, developed in part by Brown researchers, mired in controversy. (2021). Accessed: August 23, 2021: https://www.browndailyherald.com/article/2021/07/fda-approval-of-new-alzheimer-s-drug-aduhelm-developed-in-part-by-brown-researchers-mired-in-controversy
[6] Alzheimer's Association. Aducanumab approved for treatment of Alzheimer’s Disease. (2021). Accessed: August 23, 2021: https://www.alz.org/alzheimers-dementia/treatments/aducanumab
[7] U.S. Food and Drug Administration. FDA Grants Accelerated Approval for Alzheimer’s drug. (2021). Accessed: August 23, 2021: https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug

Release date:2022.10.24