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How difficult is it to conquer Alzheimer’s disease?
How difficult is it to conquer Alzheimer’s disease? Since the world’s first Alzheimer’s disease patient was discovered more than 100 years ago, scientists have never stopped exploring its pathogenesis and developing therapeutic drugs.
1. What is Alzheimer’s disease?
Alzheimer’s disease (AD) is a neurodegenerative disease with an insidious onset, and its condition will continue to worsen over time. The cognitive ability of the patient will gradually decline, the behavioral ability will continue to decline, and the memory loss will affect their normal life; at the same time, the patient needs to receive long-term comprehensive care, which brings a heavy economic burden to the family and society.
According to the “World Alzheimer’s Report 2019” issued by the International AD Association, in 2019, more than 50 million people worldwide suffer from dementia, and by 2050, the number will increase to 152 million. AD accounts for the majority of dementia, so new drugs are urgently needed in this field to slow the progression of the disease. Li Zhixin, Party Secretary of the China Centers for Chronic Noncommunicable Disease Control and Prevention, pointed out at a press conference of the National Health Commission that the prevalence of senile dementia in China is about 5.56%. Based on this estimate, current Chinese patients with senile dementia Approximately more than 9 million, it is estimated that by 2050, this number will exceed 40 million, of which about 60% will be Alzheimer’s disease.
Currently, only 6 anti-AD drugs have been approved for marketing by the FDA (tacrine, donepezil, rivastigmine, galantamine, memantine hydrochloride, donepezil + memantine compound preparation) globally.
In order to conquer AD, since 1998, the world has invested more than 600 billion US dollars in research and development expenses. Pfizer, Eli Lilly, Roche, Merck, AstraZeneca, Merck and other well-known pharmaceutical companies have invested huge amounts of money in AD drug research, but all announced failure or had to terminate the research.
Biogen’s Aducanumab is developed based on the β-amyloid (Aβ) deposition hypothesis. Aducanumab (BIIB037) is a monoclonal antibody that targets beta amyloid. It can selectively bind to amyloid deposits in the patient’s brain to reduce the accumulation of beta amyloid, thereby slowing the progression of the disease.
However, the current therapeutic targets (such as rivavastigmine, galantamine, and donepezil) are all indirect, and none of them are thought to be directly causally related to the development of AD. All these drugs are only symptomatic treatments, none of them can prevent or delay the progression of AD.
However, the clinical trial results of Aducanumab are not satisfactory. US FDA approval of drugs usually requires two valid studies with supporting evidence, while only one of the two Phase III trials of Aducanumab has shown positive results. In March 2019, the pause button was pressed for two phase III clinical trials and one important phase Ib clinical trial.
2. Why is it so difficult to develop new drugs for Alzheimer’s disease?
01) Uncertain pathogenesis
Discovering the underlying mechanism of AD and finding drugs that can prevent the pathogenic steps that lead to neuronal destruction is a very long and costly process. So far, the cause and specific mechanism of AD are not fully understood. At present, drug development is based on various hypotheses, including brain β-amyloid deposition, neurofibrillary tangles, neuroinflammation, and traumatic brain injury.
In the mainstream theories in the past, the root cause of AD is β-amyloid deposition. The formation of this view is based on the following process: Tau protein hyperphosphorylation causes extracellular accumulation of amyloid β (Aβ) plaques in the human cortex and marginal zone and the formation of intracellular neurofibrillary tangles, leading to synaptic damage and response Sexual oxidative stress increases, which in turn leads to the infiltration of microglia around the plaque area. Aβ plaques activate Toll-like receptors on microglia, leading to microglia activation and secretion of pro-inflammatory cytokines and chemokines. Microglia are activated by protein accumulation. Protein accumulation is triggered as a pathology, migrates and initiates an immune cascade response, causes neuroinflammation, and induces Tau protein fibrillary tangles, which eventually leads to neuronal death, which is reflected in the imaging of the brain Shrinking.
Based on the above theory, most treatments for Alzheimer’s disease focus on reducing the phosphorylation level of Aβ and Tau protein. The increase of phosphorylation level of Aβ and Tau protein is the extensive neurodegenerative process of early and late Alzheimer’s disease. At present, several drugs have been researched and have entered Phase 1, Phase 2 and Phase 3 clinical trials.
At this year’s AD Association International Conference, an analysis from the US anti-AD organization showed that despite the high “attenuation rate”, drugs targeting amyloid still accounted for 13 of the 32 drug candidates in advanced AD clinical trials. It accounts for about 40%, which is similar to the previous year. The remaining 19 drugs are in research ideas, from attempts to target Tau protein to mixed use of other drugs, with the purpose of protecting neurons from degeneration and blocking the inflammatory and metabolic processes related to dementia.
For many years, researchers have focused on studying the physiological phenomena of AD visible in the brain, namely, extracellular amyloid plaques and intracellular Tau protein tangles, but many treatments designed to dissolve amyloid plaques have failed in clinical trials. Failed to bring real gospel to AD patients.
Critics of the beta amyloid deposition hypothesis point out that the brains of many people without Alzheimer’s have been shown to have plaques after death. The existence of these abnormal amyloid deposits is consistent with the theory of microbial infection. In fact, the theory of microbial infection is not a substitute for the amyloid theory, but more like a supplementary explanation for the excessive production of Aβ plaques. Germany’s Alison Abbott wrote in the Nature news edition on November 4 that: Aβ was originally a hero who helped protect the brain against external infections; in the process of fighting infection, Aβ was overexpressed and became difficult to remove and cause AD.
And more and more research evidence shows that brain-gut-microbiota axis disorders can cause brain infections. Changes in the composition of the intestinal microbiota can induce an increase in the permeability of the intestinal barrier, and bacteria or their products can be transferred from the gastrointestinal tract and oral and nasal cavities to the central nervous system. Especially in the elderly, immune activation leads to systemic inflammation, and then Damage the blood-brain barrier, promote neuroinflammation, nerve damage, and ultimately lead to neurodegeneration . The regulation of the composition of the gut microbiota can be a potential therapeutic target for Alzheimer’s disease.
In November 2019, the National Medical Products Administration approved the marketing registration application of Ganlut Sodium Capsules (trade name “Nine Phase One”) for mild to moderate Alzheimer’s disease and improve the cognitive function of patients . This first new drug for Alzheimer’s disease that targets the brain-gut axis developed by a Chinese company has officially launched the enrollment of patients in an international multi-center phase III clinical trial. The screening of the first patient has been successfully completed. It is expected It will be completed in 2025. Behind the research and development logic of the “Nine Phase One” scientific research team is a new understanding of the pathogenesis of Alzheimer’s disease: neuroinflammation induced by intestinal flora disorders is an important pathogenesis of Alzheimer’s disease.
02) Insufficient stability of the drug in vivo
Another main reason for the failure of drug therapy is that the physical and chemical properties of the drug do not meet the requirements for drug efficacy (such as hydrophobicity), the unfavorable absorption of biofilms, unfavorable pharmacokinetic parameters (such as rapid plasma metabolism), and the lack of drugs. Stability (oxidation, hydrolysis or photolysis) and tissue toxicity (hepatotoxicity, neurotoxicity or nephrotoxicity), etc.
Many available drugs lose their effectiveness when crossing the blood-brain barrier, greatly reducing their bioavailability in the brain. In addition, the blood-brain barrier also has a negative impact on the efficacy and tolerability of drugs, because large doses of drugs are required to reach levels above the lowest effective concentration in the brain.
The use of drugs in the form of nanoplatforms or nanodevices can improve the pharmacokinetics and pharmacodynamic properties of the drugs, and reduce drug toxicity. An important aspect of the development of nanomedicine is the delivery of drugs and the controlled release of drugs at the diseased site. Therefore, by integrating nanotechnology-based drug delivery systems, it can be used to transport active molecules in the blood-brain barrier, thereby reducing toxicity and improving therapeutic effects . This is largely a thankless task, with more than 200 failed projects, but there are still many projects that have entered the expensive Phase III testing phase before being abandoned.
Mankind still has a long way to go to overcome Alzheimer’s disease, but fortunately, our understanding of Alzheimer’s disease is increasing day by day, and research and discovery are also constantly improving.
In the process of exploration, what we can do is not only wait for the emergence of effective treatments, adhere to a healthy lifestyle, pay attention to brain health and mental state, and strive to reduce the risk of AD. It is everyone’s responsibility.
At the same time, when treating patients with Alzheimer’s disease, we should abandon those negative and pessimistic notions, just like the theme of World Alzheimer’s Disease Month 2020-“Come calmly, never avoid it”, and care about Alzheimer’s Murder patients become conscious of action, allowing them to continue to enjoy a life of quality and dignity.