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September 21, 2023 is the 30th World Alzheimer’s Day.
Alzheimer’s disease (AD) is a neurodegenerative disease common in the elderly. The main pathological changes are diffuse atrophy of the cerebral cortex, intraneuronal fibrillary tangles, and the formation of a large number of senile plaques between nerve cells. Progressive cognitive impairment and memory loss are its main clinical symptoms.[1]
No one wants to become a patient with Alzheimer’s disease, but they may be around us, they may be relatives, or even you and me in the future.
Alzheimer's Disease It is approaching us quietly and quickly
According to the website of Alzheimer’s Disease International, one person in the world suffers from dementia every 3.2 seconds[2]. The World Health Organization reports that there were 55 million cases of dementia worldwide in 2022. This number is estimated to double every 20 years, reaching 78 million by 2030 and 139 million by 2050 globally. Among them, about 70% are Alzheimer’s disease patients.
In 2020, the international medical journal “The Lancet Public Health” published online a study on dementia in people over 60 years old in China. This study reported that there are approximately 15.07 million dementia patients in China among the elderly aged 60 and above, including 9.83 million AD patients. As China’s population ages, the number of AD patients in China is gradually increasing. It is expected that by 2025, there will be 15.5 million AD patients. The progress will accelerate in 2030, and the number of AD patients will further increase to 19.5 million. Moreover, Alzheimer’s disease has begun to show a trend of younger people, with the age of onset advancing from the originally recognized age of 65 to 55 years old.
Despite such a high prevalence and an extremely pessimistic prevalence growth trend, the global AD drug development failure rate is as high as 99.6%. Compared with cancer, another difficult problem that humans have not yet overcome, the success rate of Alzheimer’s disease drug development is only 1/47[3]. All this makes Alzheimer’s disease a public health problem that cannot be ignored.
Like patients with Alzheimer’s disease, there are successive scientists and multinational pharmaceutical giants who are also in a cruel race against time.
Our Pharmacodynamics Department can deliver multiple nervous system models based on anti-depressants, anti-Alzheimer’s drugs, sedative-hypnotic and anti-anxiety drugs, analgesics, anti-convulsants, anti-Parkinson’s drugs, and anti-schizophrenia drugs.
Good News About New Drug Research and Development Comes Frequently After 20 years of R&D, black holes finally see the light of day
On November 3, 1906, German doctor, Alois Alzheimer, first brought Alzheimer’s disease into public view. Over the past 100 years since then, various scientists and multinational pharmaceutical companies, such as Johnson & Johnson, Pfizer, Biogen and Roche have invested tens of billions dollars in an attempt to find a way out of the black hole, in the research and development of Alzheimer’s disease drugs.
In the past 20 years of R&D, 146 drugs for treating Alzheimer’s disease have entered the “endpoint” of clinical trials around the world, but only 4 have successfully entered the market. According to data from the Pharmaceutical Research and Manufacturers of America in 2018, the global cumulative R&D investment in AD treatment drugs exceeded US$600 billion from 2000-2017, and more than 300 clinical drugs failed, with a failure rate as high as 99.6%. As a result, the field of Alzheimer’s disease is considered a “research and development black hole.”
| Year | Company | Drugs | Remarks |
| 1993 | Pfizer | Tacrine | The first approved drug, a cholinesterase inhibitor, was withdrawn from the market due to adverse reactions |
| 1996 | Eisai | Donepezil | Cholinesterase inhibitors have been clinically used in more than 90 countries and regions, and are currently the only effective drugs in China that can be used for the full treatment of mild, moderate, and severe Alzheimer’s disease. |
| 2000 | Novartis | Rivastigmine | Cholinesterase Inhibitor |
| 2001 | Johnson & Johnson | Galantamine | Cholinesterase inhibitor, simultaneously activates nAChR+ and inhibits Ach activity |
| 2003 | AbbVie | Memantine | NMDA receptor inhibitors, approved for the treatment of moderate-to-severe AD, can be used in combination with cholinesterase inhibitors |
| 2021 | Biogen | Aducanumab | Anti-Aβ monoclonal antibody is the first approved Aβ-targeted therapy, but its efficacy and safety are still controversial |
| 2023 | Eisai and Biogen | Lecanemab | Anti-Aβ monoclonal antibody, FDA accelerated approval, used for early AD treatment, can delay the progression of the disease and significantly improve coverage |
The good news is that since this year, there has been frequent good news in the field of Alzheimer’s disease treatment.
On January 17, China’s National Medical Products Administration (NMPA) granted Eli Lilly’s antibody drug Donanemab injection a breakthrough drug designation for the treatment of Alzheimer’s disease for the treatment of early symptomatic AD.[4] On May 4, Eli Lilly announced that its antibody therapy Donanemab for the treatment of AD met the primary and all key secondary endpoints in the Phase 3 clinical trial TRAILBLAZER-ALZ 2, making it the most powerful Phase 3 clinical trial data for Alzheimer’s disease treatment.
On July 6, the US FDA announced that it has fully approved the launch of the new AD drug Leqembi (Lecanemab), jointly developed by Japan’s Eisai and the United States’ Biogen.
On July 17, Acumen announced topline results from the Phase 1 INTERCEPT-AD trial of ACU193 as a treatment for early Alzheimer’s disease at AAIC, which met both primary and secondary objectives. ACU193 is the first clinical-stage Aβ oligomer (AβOs)-targeted antibody therapy for early-stage AD.
On July 18, Alnylam announced positive interim results from the single-dose escalation portion of its Phase 1 clinical trial of its investigational RNAi therapy ALN-APP for the treatment of Alzheimer’s disease and cerebral amyloid angiopathy (CAA), representing a new approach to the treatment of AD that is different from monoclonal antibodies.
On August 15, Tiziana announced that its AD drug foralumab was approved for clinical use by the FDA. Foralumab is the only fully human CD3 monoclonal antibody. At the same time, local administration into the nasal cavity can be used to treat a variety of CNS diseases.
Unfortunately, both Donanemab and Leqembi only slow down the cognitive deterioration of AD patients to a certain extent, but do not cure Alzheimer’s disease. Professor Samuel Gandy of the Alzheimer’s Disease Center at the Icahn School of Medicine at Mount Sinai said, “I would like to remind patients that the benefit of this drug is to slow the patient’s cognitive decline, but patients and families should not expect to see improvement.”[5]
However, the launch of new drugs still brings hope to the treatment of AD and rekindles the flame of hope in the development of new drugs for AD.
Latest Progress in AD Target Research
The current understanding of the mechanism of Alzheimer’s disease mostly comes from the study of familial Alzheimer’s disease (fAD), which is also the basis of the amyloid hypothesis, that is, excessive aggregation of Aβ will accelerate the occurrence of Alzheimer’s disease. Although genetic evidence has strongly confirmed the central role of Aβ in Alzheimer’s disease, drugs targeting Aβ have continued to fail, causing scientists to continue to dispute the Aβ hypothesis and actively explore new therapeutic targets.
Heparan sulfate 3-O transferase, a potential new therapeutic target for Alzheimer's disease
On May 26, a research and development team led by Dr. Zhangjie Wang and Professor Jian Liu from the University of North Carolina at Chapel Hill discovered a glycosaminoglycan marker related to AD by analyzing the structure of heparan sulfate (HS) in AD brain tissue, 3-O-sulfated heparan sulfate, provideing a new molecular target for studying the progression mechanism of AD.[6]
Cdc42, a potential new target for cognitive impairment in Alzheimer's disease
On May 31, the team of Professors Lu Zhang and Lin Zhang from the School of Basic Medical Sciences of Southern Medical University published an article titled “Cdc42GAP deficiency contributes to the Alzheimer’s disease phenotype”, showing the latest research results from their research team. This study aimed to explore whether activation of the Cdc42 signaling pathway is associated with Alzheimer’s disease-like phenotypes.[7]
Alzheimer's disease reappears as new potential targets: miR-155 and IFN-γ
On June 8, in the journal Nature Neuroscience, researchers from Harvard Medical School and Boston University, School of Medicine published the latest research results, which found that the deletion of microRNA-155 (miR-155) in microglia can induce pro-MGnD responses through IFN-γ signaling, enhance phagocytosis and compression of amyloid beta (Aβ) plaques, reduce dystrophic neurites, enhance synaptic protection, and improve cognitive function[8].
Targeted regulation of liver sEH is expected to become a new target for the treatment of Alzheimer's disease
On July 3, Professor Xinhong Zhu of Shenzhen University and Guangzhou Pazhou Lab published an article in Peer-Reviewed Journal Neuron revealing that liver sEH enzyme bidirectionally regulates Aβ formation and tau protein pathology in AD disease. It was found that liver sEH regulates plasma 14,15-EET levels, which can enter the brain and directly bind to Aβ, affecting its formation, indicating the mechanism of the liver-brain axis in the progression of AD[9].
TRIM11 can be used as a potential gene therapy target for tau diseases such as Alzheimer’s
On July 28, Professor Xiaolu Yang’s team at the Perelman School of Medicine at the University of Pennsylvania published a paper in Science and found that a gene encoding the TRIM11 protein related to tau production can inhibit the progression of animal models of neurodegenerative diseases similar to Alzheimer’s disease and improve cognitive and motor abilities simultaneously. The study also identified a critical role for TRIM11 in removing protein tangles that lead to neurodegenerative diseases such as AD[10].
The history of research and development of new drugs for Alzheimer’s disease is not only a history of innovation overcoming obstacles, but also a history of mankind’s struggle against Alzheimer’s disease. Medicilon, as a rare one-stop biopharmaceutical R&D service platform in China, is also struggling in this fight without gunpowder. For AD, Medicilon Pharmacy Department’s advanced CognitionWall Discrimination Learning memory function tracking and testing system provides 24-hour uninterrupted tracking testing, which can effectively determine the memory function changes of transgenic mice with Alzheimer’s disease that are still in the early stages of the disease and eliminate the disadvantages of Morris water maze stress interference and short-time testing.
It doesn’t matter whether it’s sooner or later. We call on the public to respond to Alzheimer’s disease scientifically, gather the power of the entire society to develop more and better drugs, and give the elderly around the world a healthy and peaceful old age, so that all human beings can age wisely.
Reference：
[1] Robert P, Ferris S, Gauthier S, Ihl R, Winblad B, Tennigkeit F. Review of Alzheimer’s disease scales: is there a need for a new multi-domain scale for therapy evaluation in medical practice?. Alzheimers Res Ther. 2010;2(4):24. Published 2010 Aug 26. doi:10.1186/alzrt48
[2] https://www.alz.org/
[3] Daunert S, Sittampalam GS, Goldschmidt-Clermont PJ. Twenty-First Century Diseases: Commonly Rare and Rarely Common?. Antioxid Redox Signal. 2017;27(9):511-516.
[4]https://www.lilly.com.cn/index.html#/?path=new_release&aid=327
[5]https://www.scientificamerican.com/article/a-neurologist-answers-questions-patients-might-have-about-the-new-alzheimers-drug-lecanemab
[6]Wang Z, Patel VN, Song X, et al. Increased 3-O-sulfated heparan sulfate in Alzheimer’s disease brain is associated with genetic risk gene HS3ST1. Sci Adv. 2023;9(21):eadf6232. doi:10.1126/sciadv.adf6232
[7]Zhu M, Xiao B, Xue T, et al. Cdc42GAP deficiency contributes to the Alzheimer’s disease phenotype [published online ahead of print, 2023 May 31]. Brain. 2023;awad184. doi:10.1093/brain/awad184
[8]https://www.nature.com/articles/s41593-023-01355-y
[9]Wu Y, Dong J H, Dai Y F, et al. Hepatic soluble epoxide hydrolase activity regulates cerebral Aβ metabolism and the pathogenesis of Alzheimer’s disease in mice[J]. Neuron, 2023.
[10]https://www.science.org/doi/10.1126/science.add6696
