The new theory is that Alzheimer's disease is not a brain disease in nature, but an autoimmune disease

Written byWang Cong EditorWang Duoyu typesettingWater into the text

There may be no disease like Alzheimer's disease, which leads countless heroes to bend their backs
.

Even international pharmaceutical giants such as Pfizer, Johnson & Johnson, Roche and others find it tricky, and the world's major pharmaceutical companies have not succeeded
after spending tens of billions of dollars on clinical trials of drugs for these two targets.

Alzheimer's disease (AD), commonly known as "Alzheimer's disease", is a serious neurodegenerative disease, patients usually have memory decline, learning ability to weaken the main symptoms, accompanied by emotional regulation disorders and loss of athletic ability, greatly affecting the development of
individuals, families and even society.

Currently, about 50 million people worldwide suffer from Alzheimer's disease
.

As the average human life expectancy increases and an aging society intensifies, the prevalence of Alzheimer's disease is also rising, and it is expected that by 2050, the number of Alzheimer's disease patients will increase to more than
150 million.

Unfortunately, due to the complexity of the etiology, the scientific community has not yet deciphered the specific mechanism of the onset of Alzheimer's disease, and the mainstream view is that the cause is β-amyloid (Aβ) and Tau protein deposition resulting in a large number of neuronal deaths
.

The field of Alzheimer's disease is constantly controversial

The entire field of Alzheimer's disease drug development is highly competitive and controversial
.

In particular, some recent controversial events have made Alzheimer's disease the focus of
public opinion.

On July 22, 2022, Science published a six-month investigation report that said that Sylvain Lesné, a neuroscientist at the University of Minnesota, may have academic misconduct in more than 20 papers, including an important paper
in the field of Alzheimer's disease published in Nature in 2006.

The report notes that the alleged β amyloid oligomer Aβ*56 found in the Nature paper that causes Alzheimer's disease is most likely absent
.

This study is likely to mislead Alzheimer's disease research around the world for 16 years
.

More than a year ago, in June 2021, the FDA announced an accelerated approval of Biogen's monoclonal antibody drug aducanumab (trade name Aduhelm) for the treatment of Alzheimer's disease-induced mild cognitive impairment (MCI) and mild Alzheimer's disease
.

It is the first new drug approved by the FDA for the treatment of Alzheimer's disease since 2003 and the first drug to claim to stop the progression of the disease
.



However, the approval of the drug has caused great controversy, and clinical trials have shown that although it can remove β-amyloid (Aβ) from the brain, there is not enough evidence that it can slow or stop the progression
of Alzheimer's disease.

Not only that, but the results of a Phase 3 clinical trial subsequently published in the journal JAMA Neurology showed that the drug had significant side effects, with more than one-third of patients developing cerebral edema
after the administration.


However, there are still tens of millions of people around the world suffering from Alzheimer's disease, and the successive failures, what is the problem? Breaking away from the β-amyloid stereotype
for years, scientists have worked to treat Alzheimer's disease and stop or slow disease progression
by stopping this mysterious protein-forming team called β-amyloid (Aβ) and its damage to the brain.


Unfortunately, years of heavy investment in Abeta have not translated into useful drugs or therapies
.

Perhaps scientists are getting caught up in an overfocus on Aβ and ignoring other possible causes
.


Therefore, jumping out of the box and revisiting Alzheimer's disease is becoming a new frontier
in Alzheimer's disease research.


Donald Weaver et al.
of Dalhousie University in Canada recently published papers in the journal Alzheimer's & Dementia: Translational Research & Clinical Interventions
.


Based on his team's 30 years of Alzheimer's research, he proposed a new theory: Alzheimer's disease is not essentially a brain disease, but an autoimmune disease
that occurs mainly in the brain.

The immune system is present in every organ in our body, and they work in harmony to help repair damage and protect against foreign invaders
.

When you are injured, the immune system helps repair the damaged tissue
.

When you experience a viral or bacterial infection, the immune system goes back to help fight these invaders
.


The same is true in the brain, where the brain's immune system initiates repair when the head is traumatized
.

When a bacterial or viral infection appears in the brain, the immune system also fights back
.

Is Alzheimer's disease an autoimmune disease? Donald Weaver's team believes that β-amyloid (Aβ) is not an abnormally produced protein, but a normally present part of
the brain's immune system.


When brain damage occurs or is infected by bacteria, β-amyloid (Aβ) is a key factor
in the brain's comprehensive immune response.

Due to the high similarity between the lipid molecules that make up bacterial cell membranes and the lipid molecules of brain cell membranes, Aβ is unable to distinguish who is invading bacteria and who is brain cells, resulting in a false attack
on brain cells.

This false attack leads to a chronic progressive loss of brain cell function, which eventually leads to dementia
.

And all because our body's immune system can't distinguish between invading bacteria and brain cells
.


Therefore, the research team believes that Alzheimer's disease is essentially an autoimmune disease
caused by the immune system making a wrong attack on the brain that should be protected.


The human brain is a very special organ with what is recognized as the most complex structure
known in the universe.

In the study's model of Alzheimer's disease, the team found that β-amyloid (Aβ) helps protect and strengthen the immune system, but unfortunately, Aβ also plays a central role in autoimmunity, thus contributing to the development of
Alzheimer's disease.
The research team believes that while traditional drugs that treat autoimmune diseases may not be effective against Alzheimer's disease, other immunomodulatory pathways that target the brain may find new and effective treatments
from them.


In addition to the theory of this autoimmune disease, a series of new theories of
Alzheimer's disease have been proposed in recent years
.


For example, some research teams believe that Alzheimer's disease is a disease of abnormal mitochondrial structure, and mitochondria are energy factories within cells, converting the oxygen we breathe and the glucose in the food we eat into the energy
needed for life.

They believe that it is abnormal mitochondrial structure in brain cells that causes Alzheimer's disease
.


In addition, there are studies that believe that Alzheimer's disease is caused by a specific brain infection (such as an infection of bacteria in the mouth).


There are also studies suggesting that Alzheimer's disease may be caused by abnormal processing of metallic elements (possibly zinc, copper, iron) in
the brain.
In March 2022, the Yuan Augmentation team of the Academy of Military Medicine collaborated with Luyang Sun of Peking University to publish a paper
in the journal Cell Metabolism.

A new mechanism of epigenetic regulation of Alzheimer's disease is proposed, and the vicious cycle of "glycolysis-histone lactoacidation-PKM2" formed by microglia metabolic disorders can lead to the occurrence of microglial homeostasis imbalance and neuroinflammation, which in turn promotes the development of
Alzheimer's disease.
New Alzheimer's disease therapy At present, 50 million people in the former world are suffering from Alzheimer's disease, with the acceleration of population aging, Alzheimer's disease is in a public health crisis, we need to innovate ideas and expand new directions to achieve the treatment
of Alzheimer's
disease.


In August 2022, researchers from the Korea Academy of Science and Technology (KAIST) published a paper in Nature Medicine
.

The study developed a novel fusion protein drug, αAβ-Gas6, which effectively clears Aβ from the brain through a completely different mechanism from that of Aβ
monoclonal antibody.

In a mouse model of Alzheimer's disease, αAβ-Gas6 not only better clears Aβ, but also circumvents the neurotoxic inflammatory side effects
associated with conventional antibody therapy 。 Based on this research result, the research team founded a company called Illimis Therapeutics, through which the research team plans to further develop various Gas6 fusion proteins for the elimination of Aβ, Tau, etc.
, for the treatment of a variety of neurological diseases including Alzheimer's disease and autoimmune diseases affected by toxic proteins, which is expected to become a new treatment platform
.

In September 2022, Professor Ann Zhiqiang's team at the University of Texas at the Houston Health Science Center published a paper
in the journal Science Translational Medicine.


The team developed a quadrivalent TREM2 agonist antibody that has shown therapeutic effects both in vitro and in mouse models of Alzheimer's disease, including increasing microglia-mediated phagocytosis and improving animal cognition
.

Studies have shown that the antibodyBody-mediated TREM2-targeted therapy is effective in reducing the pathology of Alzheimer's
disease.

In January 2022, the Fang Fei team at the University of Oslo in Norway collaborated with the Lu Jiahong team of the University of Macau to publish a paper
in the journal Nature Biomedical Engineering.


In 2019, Fang Fei's team published a paper in Nature Neuroscience, demonstrating that damage to the mitochondrial clearance mechanism (mitochondrial autophagy) plays a key role
in the onset of Alzheimer's disease.

On this basis, Fang Fei/Lu Jiahong's team screened a large number of small molecules through machine learning, and found that 2 pilot small molecule compounds such as kaempferol and danye emodin can induce autophagy in nerve cells, which has the potential
to treat Alzheimer's disease.

In December 2021, Cheng Feixiong's team at Cleveland Medical Center published a paper in the journal Nature Aging
.


The study found that sildenafil, a drug that treats pulmonary hypertension and erectile dysfunction in men, is associated
with a significantly lower risk of Alzheimer's disease.

The results of this study suggest that sildenafil is an option
for new use or treatment of Alzheimer's disease.

Paper link: https://alz-journals.
onlinelibrary.
wiley.
com/doi/10.
1002/trc2.
12283
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