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Alzheimer's disease: Who's to blame?

 In June 2021, the US Food and Drug Administration (FDA) approved a new treatment for Alzheimer's disease, the first time a treatment for the disease has been approved in nearly two decades. But some experts are unhappy because the results of clinical trials of the approved drug, Aducanumab, do not show that it slows cognitive decline.


Each of the hand-stitched illustrations by alzheimer's patients represents a different stage of the disease and the emotions sufferers may feel, from sadness and confusion to pain and anger. The final illustration illustrates not only the loss of memory, but also the loss of identity...


The FDA approved the drug based on evidence that it treats the underlying cause of Alzheimer's disease. The problem is that the drug targets beta-amyloid plaques, but scientists don't know if the protein is actually responsible. Scientists are right to be concerned about the new drug, given that previous trials of drugs targeting the protein have failed repeatedly, with some causing cognitive deterioration in patients. Their biggest concern is that continuing to focus solely on amyloid beta, a potential cause of the disease, is discouraging the development of drugs that can actually fight Alzheimer's, obscaring the complex nature of the disease and wasting precious time.

Scientists are increasingly inclined to believe that there is no single cause of Alzheimer's disease. This may not seem like good news, but many different risk factors could offer multiple approaches to treatment.

Past knowledge


About two-thirds of the 10 million new cases of dementia that occur worldwide each year are Alzheimer's disease. Although the exact cause of the disease is unclear, scientists have focused most of their attention on one factor, beta-amyloid.

The amyloid hypothesis became popular in the 1990s when scientists discovered three rare genetic mutations involved in the formation of beta-amyloid. Patients with either mutation generally develop the disease before age 65. Because of the presence of beta-amyloid plaques in patients' brains, scientists thought beta-amyloid was responsible for the disease, while other factors were linked to a cascade of beta-amyloid products.


Amyloid is a protein aggregate that is 7-13 nanometers in fibrous form


The role of beta-amyloid in Alzheimer's disease is similar to the role of cholesterol in heart disease. In both cases, levels of the protein, or cholesterol, rise for decades before symptoms appear. If abnormally high cholesterol levels are detected early and drugs are given to lower them, the development of heart disease can be prevented. But once the heart is damaged, drugs can't reverse it. Alzheimer's disease develops in a manner similar to heart disease, in which anti-amyloid drugs do not reverse the disease, but may be effective if taken before symptoms appear.


In alzheimer's disease, neurons in the brain are damaged by amyloid


Neurons affected by Alzheimer's disease. Neuronal degeneration is associated with the formation of intercellular tau proteins (pink) as well as extracellular beta amyloid, which forms amyloid plaques (top right)

Entanglements with tau proteins


Another major marker of Alzheimer's disease is an accumulation of a protein in the brain called tau. The tau protein is designed to support the structure of neurons, but certain changes can cause it to accumulate abnormally and interfere with normal communication. Tau protein is important in the development of Alzheimer's disease. Once symptoms of Alzheimer's disease have developed, tau levels are more closely associated with disease severity than beta-amyloid. Therefore, some studies believe that it may be more feasible to target tau protein in the later stage of the disease.

But since most of the tau protein is formed inside neurons, finding its target has been difficult. In addition, there are many different forms of tau, and it is not clear which one is the most effective target for treatment. While there are currently no alzheimer's drugs that target tau, steps can be taken in daily life to reduce the risk of accumulating harmful tau tangles. For example, activities, foods or lifestyles that are good for the heart are often good for the brain as well.

Genetic mutations are accomplices


About 5 percent of Alzheimer's is early-onset, and while only a small fraction of those are caused by mutations, many genetic mutations have been linked to late-onset Alzheimer's. These mutations cause apolipoprotein E (APOE) to produce two variants, one of which, APOEe2, lowers the risk of the disease and the other, APOEe4, increases it.

According to the study, APOEe4 may promote the formation of beta-amyloid plaques and may also contribute to neuroinflammation that affects blood-brain barrier function. At the moment, humans can't easily modify their own genes, and testing for APOE mutations isn't necessary because they don't necessarily cause Alzheimer's -- many people with APOEe2 will still develop Alzheimer's, while many people with APOEe4 will never develop it.


The pathogen is an accomplice


The infection may also increase a person's risk of developing Alzheimer's disease. For example, a study of nearly 30,000 people showed that people who had had serious dental problems for at least 10 years had about a 70 percent increased risk of developing Alzheimer's disease. After the patients died, scientists found porphyromonas gingivalis, one of the bacteria responsible for tooth disease, and the toxic enzymes it produces in their brains.

In experiments on mice, scientists have found that porphyromonas gingivalis can migrate from the mouth to the brain. They gave mice a drug that effectively blocked the action of the toxic enzyme and reduced levels of beta-amyloid protein in their brains. Based on the results, scientists have recruited more than 600 patients with mild to moderate Alzheimer's to participate in a clinical trial of the drug, the results of which are expected soon. Although there is no direct evidence of a link between oral hygiene and the risk of Alzheimer's disease, regular brushing, flossing and regular visits to the dentist are beneficial.


Pay attention to improving sleep quality


A growing body of research links Alzheimer's disease to sleep problems, and suggests that the relationship probably goes both ways.

When we sleep, harmful proteins produced by metabolism are removed by the brain's waste removal apparatus, the lymphoid system. Sleep is important for protecting the brain, because even one night without sleep can dramatically increase levels of beta-amyloid in the brain. Lack of sleep also promotes the buildup of tau protein and inflammation in the brain. Therefore, we can reduce our risk of Alzheimer's disease by improving sleep quality. Scientists recommend getting at least seven hours of sleep a night and developing good sleep habits, such as keeping a regular bedtime and avoiding bright light and drinking strong tea or coffee in the evening.


Brain damage can also have side effects


Brain damage increases the risk of Developing Alzheimer's disease later in life. A study of more than 350,000 people has found that even minor head injuries can more than double the risk of developing Alzheimer's disease later in life.

Symptoms of Alzheimer's disease overlap with those of traumatic brain injury (TBI), but there is no conclusive evidence of a relationship between the two. It is important to emphasize that TBI is only one of many risk factors for developing the disease, and that even those who have suffered FROM TBI are only at greater risk. Most TBI patients do not develop alzheimer's disease after recovery.

If you are unlucky enough to suffer FROM TBI, you can help protect your brain health after brain injury by eating a healthy diet, practicing good sleep habits, exercising, and staying socially active, but there are limits to how effective these measures can be in treating long-term brain injury symptoms. Therefore, it is important to prevent head trauma, such as wearing a helmet when riding a motorcycle and checking your eyesight regularly to prevent falls.


Multi-pronged approach is more effective


A growing number of studies have concluded that Alzheimer's disease does have multiple causative factors. There are many pathologies that lead to cognitive impairment, and the reason scientists haven't developed a truly effective drug to treat Alzheimer's disease is that for the past 30 years they have focused almost exclusively on removing beta-amyloid.

It is also unwise to focus on another single cause, because all factors are combined and a single factor cannot explain the whole picture of Alzheimer's disease. This new understanding has begun to change the way scientists study the disease and share data. For example, the Global Alzheimer's Association Interactive Network and Neural Database, launched in 2019 by the European Union's Innovative Medicines Initiative, aim to promote collaboration and data sharing to promote a more comprehensive understanding of neurodegenerative diseases, including Alzheimer's disease.

Given the complexity of the causes of Alzheimer's disease, a multifaceted approach may be the only way to truly understand and treat it. Scientists believe that controlling for known risk factors -- beta-amyloid, tau, apolipoprotein E, foreign pathogens, sleep deprivation and brain damage -- should reduce the incidence of Alzheimer's by about 30 percent.


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