HOW hard is it to conquer Alzheimer's?

Since the discovery of the world's first case of Alzheimer's more than 100 years ago, scientists have never stopped exploring its pathogenesis and developing therapeutic drugs.
, what is Alzheimer's? Alzheimer's disease (AD) is a hidden neurodegenerative disease that worsens over time.
patients' cognitive abilities will gradually decline, their behavior will decline, their memory will be lost, and their normal lives will be affected, while patients will need long-term comprehensive care, which will put a heavy financial burden on the family and society.
more than 50 million people worldwide will have dementia in 2019 and the number will rise to 152 million by 2050, according to the World Alzheimer's Report 2019, released by the International Association of ADs.
AD accounts for the majority of dementia, there is an urgent need for new drugs to slow the progression of the disease.
Li Zhixin, secretary of the Party Group of the CDC's Chronic Noncommunicable Diseases Prevention and Control Center, previously pointed out at a meeting of the National Health And Wellness Commission that the prevalence of dementia in China is about 5.56 percent, according to which it is estimated that there are now more than 9 million people with dementia in China, and that number is expected to exceed 40 million by 2050, about 60 percent of whom are Alzheimer's disease.
currently, only six anti-AD drugs are approved by the FDA worldwide (ticklin, Donaphate, kabaratin, galantamine, hydrochloric acid meth, donna pyridodin and meth compound preparations).
to conquer AD, the company has invested more than $600 billion in research and development worldwide since 1998.
well-known pharmaceutical companies, including Pfizer, Lilly, Roche, Mercer East, AstraZeneta and Merck, have invested heavily in AD drug research, but have failed or had to terminate it.
Aducanumab, based on β hypothesis of amyloid protein (A beta) deposition.
Aducanumab (BIIB037) is a monoclonal antibody that targets β amyloid proteins and selectively binds to amyloid deposition in the patient's brain, reducing the build-up of β amyloid proteins, thereby slowing disease progression.
monoantigen binding schematics (photo source: Network) However, current therapeutic targets such as Devas Ming, Galantamine, and Donaizi are indirect, and none is thought to have a direct causal relationship with the development of AD.
all of these drugs are just treatments for the disease, none of which can stop or delay the progression of AD's disease.
but Aducanumab's clinical trial results are not ideal.
FDA-approved drug typically requires two effective studies with supporting evidence, while only one of the two Phase III trials of Aducanumab has shown positive results.
March 2019, two Phase III clinical trials and an important Phase I clinical trial were pressed the pause button.
, why is it so difficult to develop new drugs for Alzheimer's? The pathogenesis of 01 is uncertain about the potential mechanisms for finding AD and finding drugs that can block the pathogenic steps that cause neuron damage.
So far, the cause and specific mechanism of AD is not completely clear, the current drug research and development is based on a variety of hypothesis theories, including brain β amyloid deposition, nerve fiber entanglement, nerve inflammation, brain trauma and so on.
in past mainstream theories, the root cause of AD is β deposition of amyloid proteins.
The formation of this view is based on the following process: Tau protein excessive phosphate causes amyloid β (A beta) plaques in the human cerebral cortit and edge area of the extracellular aggregation and the formation of intracellular neurogenic fiber tangles, resulting in synaptic damage and increased reactive oxidative stress, which in turn leads to small glial cells around the patch region.
A beta plaque activates Tol-like subjects on small glial cells, leading to activation of small glial cells and the secretion of inflammatory cytokines and degeneration factors.
Small glial cells are activated by protein accumulation, which actes as a pathological trigger, migrates and initiates an immune cascade response, causes nerve inflammation, and induces the production of Tau protein fiber entanglements, which eventually lead to neuron death, reflected in imaging brain atrophy.
Based on the above theory, most treatments for Alzheimer's disease focus on reducing phosphorylation levels of A beta and Tau proteins, which are widespread neurodegenerative processes in early and late Alzheimer's disease.
several drugs have been studied and have entered Phase I, Phase II and Phase III clinical trials.
Analysis from the U.S. Anti-AD Organization at this year's AD Association International Conference showed that despite the high "decompression rate," drugs targeting amyloid still accounted for 13 of the 32 candidates for advanced AD clinical trials, or about 40 percent, about the same proportion as the previous year.
the remaining 19 drugs in the study, from attempts to target Tau proteins to a mix of other drugs, are designed to protect neurons from degeneration and block inflammation and metabolic processes associated with dementia. For more than
years, researchers have focused on the physiological phenomena that AD can see in the brain, i.e. extracellular amyloid plaques and in-cell Tau protein tangles, but many treatments designed to dissolve amyloid plaques have failed in clinical trials and failed to bring real good news to AD patients.
β of the amyloid deposition hypothesis point out that the brains of many people who do not have Alzheimer's disease are also shown to contain plaques after death.
the presence of these heterogeneic amyloid protein deposits, consistent with microbial infection theory.
fact, microbial infection theory is not a substitute for amyloid theory, but more of a complementary explanation for the excessive production of A-beta plaques.
Alison Abbott of Germany wrote in the Nature news section on November 4th that A-beta was originally intended to help protect the brain from foreign infections;
and growing research suggests that brain-intestinal-microbiome axis disorders can cause brain infections.
Changes in the composition of the gut microbiome can induce an increase in the permeability of the intestinal barrier, and bacteria or their products can be transferred from the gastrointestinal tract and mouth and nasal cavity to the central nervous system, especially in the elderly population, where immuno-activeness leads to systemic inflammation, which in turn damages the blood-brain barrier, promotes nerve inflammation, nerve damage, and ultimately neurodegeneration.
the composition of the gut microbiome can be a potential therapeutic target for Alzheimer's disease.
the State Drug Administration in November 2019 conditionly approved the listing application for the ganlute sodium capsule (the trade name "Nine Phase One") for mild to moderate Alzheimer's disease to improve patient cognitive function.
The first new drug for Alzheimer's disease, developed by a Chinese company, has recently officially launched an international multi-center Phase III clinical trial for patients, and the first patient screening has now been successfully completed and is expected to be completed by 2025.
behind the development logic of the "Nine Phase Ones" research team is a new understanding of the pathogenesis of Alzheimer's disease: neuroinstillation induced by intestinal bacteriologic disorders is an important pathogenesis of Alzheimer's disease.
02 Another major reason for the failure of drug treatment with insufficient stability in the drug body is that the physicochemical properties of the drug do not meet the requirements for the effects of the drug (e.g. hydrophobic), adverse absorption of biofilms, adverse pharmacodynamic parameters (e.g. rapid plasma metabolism), drug instability (oxidation, hydrolysis or photolysis) and toxicity to tissues (hepatotoxicity, neurotoxicity or nephrotoxicity).
many of the drugs available are ineffective when they cross the blood-brain barrier, greatly reducing bio-use in the brain.
addition, the blood-brain barrier has a negative impact on drug efficacy and tolerance, as large doses of the drug are needed to reach levels above the lowest effective concentration in the brain.
use of drugs in the form of nano-platforms or nano-devices can improve the pharmacodynamic and pharmacological properties of drugs and reduce drug toxicity.
aspect of the development of nanomedical science is the delivery of drugs and the release of drugs at the disease site.
, 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 treatment effectiveness.
this is largely an unflattering task, with more than 200 failed projects, many of which entered the expensive Phase III testing phase before being abandoned.
there is still a long way to go before humans can overcome Alzheimer's disease, but thankfully our understanding of Alzheimer's is growing and research and discovery is improving.
in the process of exploration, we can do more than just wait for effective therapies to emerge, adhere to a healthy lifestyle, pay attention to brain health and mental state, and strive to reduce the risk of AD, is everyone's responsibility.
At the same time, we should reject negative and pessimistic ideas about Alzheimer's patients, as the theme of World Alzheimer's Day 2020 writes - "Face it, don't shy away" - and turn caring for Alzheimer's patients into a conscious act, so that patients can continue to enjoy a quality, dignified life."
references: Tiwari S, Atluri V, Kaushik A, Yndart A, Nair M. Alzheimer's disease: pathogenesis, diagnostics, and therapeutics. Int J Nanomedicine. 2019 Jul 19; 14:5541-5554. J Neurogastroenterol Motil. 2019 Jan 31;25 (1):48-60. Hsiao IL, Hsieh YK, Chuang CY, Wang CF, Huang YJ. Effectsof silver nanoparticles on the interactions of neuron-and glia-like cells: toxicity, uptake mechanisms, and lysosomal tracking. Environ Toxicol. 2017;32 (6): 1742-1753