文:鄭靖蓉 / 聚和國際 R&D 實習生

History and research progress of Alzheimer's disease

Alois Alzheimer examination of patients in 1906 found that not only amyloid plaques were present in the brain, but also that the brain had lost a large number of neurons. Subsequently, it was also found that the patient had symptoms of memory loss and personality changes before death, so Alois Alzheimer described the condition as a serious disease of the cerebral cortex. Dr. Emil Kraepelin then named the disease Alzheimer's disease (AD) for the first time in his 8th edition of the Psychiatric handbook [1].

Alzheimer is a neurodegenerative disease that accounted for more than 80% of global dementia cases in the elderly in 2014. Alzheimer's disease leads to mental, behavioral, functional decline, and gradual loss of learning ability [2]. By January 2021, about 50 million people worldwide will be living with Alzheimer's disease. Studies estimate that this will increase to 152 million people by 2050. There are currently no drugs that can treat Alzheimer's, just only improve its symptoms [1].

Exploring the causes of Alzheimer's disease: the role of genes, environment and lifestyle

Alzheimer's is considered a disease associated with a variety of risk factors, such as age, genetic factors, head injuries, vascular disease, infections, and environmental factors (heavy metals, trace metals, diet, etc.). According to statistics collected globally, women are easier to get Alzheimer's disease than men. People with cardiovascular disease, hypertension, and diabetes are also at higher risk of developing the disease later in life [1] [3].

Insights into the pathology of Alzheimer's disease: from neuron loss to brain shrinkage

In pathology, the symptoms of AD are mainly divided into three types: intracellular neurofibrillary tangles caused by over phosphorylated Tau proteins, extracellular β-amyloid protein (Aβ) deposition leading to age spots, and synaptic damage leading to memory impairment. The mechanisms of synaptic damage are extensive, such as mitochondrial damage, oxidative stress, and the accumulation of Aβ and Tau proteins at synaptic sites, which ultimately lead to dendrite, end-of-synaptic, and axon malnutrition (Figure 1).

(Figure 1)
a. Healthy brain and 1b. The physiology of the brain and neurons in the Alzheimer's (AD) brain [1].

Future prospects for aducanumab

Although studies have proposed many hypotheses that cause Alzheimer's disease, only two are thought to be the main causes, namely the impairment of cholinergic function and the production of amyloid β proteins. However, there is no accepted theory to explain the pathogenesis of AD [1] [3].

Currently approved by the FDA for the treatment of AD are Acetylcholinesterase inhibitor and N-methyl-D-aspartate antagonists (NMDA). According to the cholinergic hypothesis, Alzheimer's disease is caused by a decrease in the synthesis of Acetylcholine (AChE), so by inhibiting Acetylcholinesterase (AChE), Acetylcholine can be synthesized and continuously accumulated. NMDA can stimulate CA2+ inflow, activate signal transduction, and activate synaptic neurotransmission and memory formation [1].

In 2016, Biogen first published the results of the Aducanumab Phase I clinical trial in the journal Nature. Aducanumab, a human monoclonal antibody, has been shown to be able to cross the blood-brain barrier in response to Aβ aggregates and clear Aβ from transgenic mouse brains with plaques. The removal of Aβ not only reduces amyloid plaque, but also improves cognitive and mental function in treated subjects [4]. But at the end of 2020, Aducanumab's Phase III clinical trial saw no significant improvement. The U.S. Food and Drug Administration (FDA) decided that the trial might not meet the criteria for clinical evaluation and temporarily suspended Aducanumab's subsequent trial.

Until June 7, 2021, the FDA provisionally approved Aducanumab for the treatment of mild cognitive impairment caused by Alzheimer's disease [5]. However, the approval of this anti-amyloid therapy has encountered considerable controversy, especially in the evidence, interpretation and application of the safety and efficacy of Aducanumab. The FDA approved primarily because it was found that there was a decreasing trend in Aβ plaques in the brains of treated patients, but there was no credible clinical data to prove it [5].
 

Therefore, Biogen will have to demonstrate the drug's safety and effectiveness in patients of different races in the next Phase 4 trial. More research is also needed to verify whether the treatment of Aducanumab is clinically relevant [5].

References

[1] Breijyeh, Z.; Karaman, R. (2020).Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules.25,5789. doi：10.3390/molecules25245789
[2] Kumar A, Singh A, Ekavali. (2015).A review on Alzheimer's disease pathophysiology and its management: an update. Pharmacol Rep. 67(2):195-203. doi: 10.1016/j.pharep.2014.09.004.
[3] Srivastava S, Ahmad R, Khare SK. (2021). Alzheimer's disease and its treatment by different approaches: A review. Eur J Med Chem .216:113320. doi: 10.1016/j.ejmech.2021.113320.
[4] Sevigny, J., Chiao, P., Bussière, T. et al. (2016).The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature .537:50–56.doi：10.1038/nature19323.
[5] Day GS, Scarmeas N, Dubinsky R, Coerver K, Mostacero A, West B, Wessels SR, Armstrong MJ. (2022). Aducanumab Use in Symptomatic Alzheimer Disease Evidence in Focus: A Report of the AAN Guidelines Subcommittee. Neurology. 98(15):619-631. doi: 10.1212/WNL.0000000000200176.