Dutch scientists have discovered five biological variants of Alzheimer's disease, which may require different treatments. As a result, previously tested drugs may mistakenly appear to be ineffective or only minimally effective. This is the conclusion of researcher Betty Tijms and colleagues from the Alzheimer Center Amsterdam, UMC Amsterdam and Maastricht University.
The result of the study was published in Nature Aging.
Biological variants of Alzheimer's disease that may require new therapies
In people with Alzheimer's disease, amyloid and tau proteins accumulate in the brain. In addition to these lumps, other biological processes such as inflammation and nerve cell growth are also involved. Using new techniques, the researchers were able to measure these other processes in the cerebrospinal fluid of patients with amyloid and tau clots.
Betty Tijms and Pieter Jelle Visser examined 1,058 proteins in the cerebrospinal fluid of 419 people with the disease. They found that five biological variants exist within this group. The first variant is characterized by increased production of amyloid. In a second type, the blood-brain barrier is disrupted, resulting in reduced amyloid production and less nerve cell growth.
In addition, the variants differ in the degree of protein synthesis, the functioning of the immune system, and the functioning of the organ that produces cerebrospinal fluid. Patients with different variants of Alzheimer's also showed differences in other aspects of the disease. For example, researchers found a more rapid course of the disease in some subgroups.
The findings are of great importance for drug research. They could mean that a certain drug might only work in a variant of Alzheimer's disease. For example, drugs that inhibit amyloid production may work in the variant with increased amyloid production, but may be harmful in the variant with reduced amyloid production.
It is also possible that patients with one variant have a higher risk of side effects, whereas that risk would be much lower with other variants.
The next step for the research team will be to demonstrate that Alzheimer's variants actually react differently to drugs, in order to treat all patients with appropriate drugs in the future.
Alzheimer's disease: the importance of the metabolic sensor
It is known that people with type 2 diabetes are at increased risk of developing Alzheimer's disease, but the reason is not fully understood and is a current area of research.
Scientists at Wake Forest University School of Medicine have discovered a new mechanism that shows that increased sugar intake and increased blood glucose are enough to cause the buildup of amyloid plaques in the brain, which increases the risk of disease . Amyloid plaque is made up of toxic proteins in the brain.
“We wanted to better understand the metabolic changes in diabetes that put the brain at risk for Alzheimer's disease or accelerate pathology already forming in the brains of individuals who will be diagnosed with Alzheimer's disease,” said Shannon Macauley, Ph.D. ., associate professor of physiology and pharmacology at Wake Forest University School of Medicine and principal investigator of the study.
Using a mouse model, the research team demonstrated that more amyloid plaques form when sugar water is given instead of regular drinking water. They also found that increasing blood sugar levels increases the production of beta-amyloid in the brain.
This finding is significant because it shows that consuming too much sugar is enough to cause the proliferation of amyloid plaque and increase the risk of Alzheimer's disease,” Macauley said.
To better understand the molecular drivers of this phenomenon, the research team identified a metabolic sensor on neurons that links changes in metabolism with neuronal activation and beta-amyloid production.
The sensors are known as adenosine triphosphate (ATP)-sensitive potassium channels or ATP K channels. ATP is a source of energy that all living cells need to survive. These channels detect how much energy is available for healthy functioning. Disrupting these sensors changes the way the brain functions normally.
“Using genetic techniques in mice, we removed these sensors from the brain and showed that increasing blood sugar no longer increased beta-amyloid levels or the formation of amyloid plaques,” Macauley said.
Next, the researchers explored the expression of these metabolic sensors in the human Alzheimer's disease brain and again found that the expression of these channels changes with a diagnosis of Alzheimer's disease.
According to Macauley, the study suggests that these metabolic sensors could play a role in the development of Alzheimer's disease and could ultimately lead to new treatments.
“What is most notable is that pharmacological manipulation of these ATP K channels may have a therapeutic benefit in reducing amyloid beta pathology for diabetic and prediabetic patients,” Macauley said.
According to the Alzheimer's Association, the disease is the most common form of dementia, accounting for 60% to 80% of dementia cases. While current research suggests that alcohol use disorder is a risk factor, the impact that alcohol use disorder has on pathology is an ongoing area of research.
In a new preclinical study, scientists at Wake Forest University School of Medicine have shown that even modest amounts of alcohol can accelerate brain atrophy, or the loss of brain cells, and increase the number of amyloid plaques, or the buildup of toxic proteins in the body.
“These findings suggest that alcohol may accelerate the pathological cascade of Alzheimer's disease in its early stages,” said Shannon Macauley, Ph.D., associate professor of physiology and pharmacology at Wake Forest University School of Medicine.
The study was a collaboration led by Macauley and Jeffrey Weiner, Ph.D., professor of physiology and pharmacology at Wake Forest University School of Medicine, through the medical school's Alzheimer's Disease Research Center and Translational Alcohol Research Center.
Using mouse models of Alzheimer's disease-related pathology, the researchers used a 10-week chronic drinking approach in which mice were given the choice of drinking water or alcohol, mimicking human behavior regarding alcohol consumption. They then explored how voluntary, moderate alcohol consumption altered healthy brain function and behavior and whether it altered the pathology associated with the early stages of the disease.
Researchers have found that alcohol increases brain atrophy and causes an increase in the number of amyloid plaques, including an increased number of smaller plaques, potentially setting the stage for greater plaque proliferation in later life.
Interestingly, the researchers also noted that acute alcohol withdrawal increases levels of beta-amyloid, which is a key component of the amyloid plaques that build up in Alzheimer's disease.
Further analysis showed that chronic alcohol exposure misregulates brain and peripheral metabolism, another way to accelerate the pathology of the disease. Macauley had previously shown that high blood sugar levels increase beta-amyloid and amyloid plaques.
In the current study, researchers found that even moderate drinking causes increases in blood sugar and markers of insulin resistance, which increase the risk not only of Alzheimer's disease but also other diseases such as type 2 diabetes and cardiovascular disease .
The study also found that moderate alcohol consumption alters behaviors related to anxiety and dementia.
“These preclinical findings suggest that even moderate alcohol consumption can cause brain damage,” Macauley said. “Alcohol consumption may be a modifiable risk factor for Alzheimer's disease and dementia.”
Some of the genes affected by alcohol and inflammation are also implicated in processes that eliminate amyloid beta, the protein that forms plaques in the brain and contributes to the neuronal damage and cognitive impairment associated with the disease.
Previous studies investigating the effects of alcohol consumption on Alzheimer's disease have been controversial: some have indicated that alcohol has a protective effect, while others have highlighted a deleterious role of alcohol in the development of this neurocognitive disease.
Recent research has suggested that alcohol consumption, and its impact on the immune system and inflammation in the brain, may be the vehicle through which alcohol may exert its influence on the development of the disease, but no previous studies have assessed directly which genes are affected. from alcohol into brain cells involved in protection against disease.
Dr. Douglas Feinstein, professor of anesthesiology at the University of Illinois at Chicago College of Medicine, along with other researchers conducted a cellular study that suggests alcohol may prevent the clearance of amyloid beta in the brain.
Feinstein and his colleagues wanted to determine which genes were affected by both alcohol and high levels of inflammation in microglial cells. These are cells that support neural cells in the brain and other parts of the body. One of their functions is to phagocytose and digest the plaques of amyloid beta protein characteristic of the disease in a process known as phagocytosis. Microglial cells are also known to express high levels of inflammatory markers due to chronic alcohol exposure.
The researchers exposed rat microglial cells to alcohol, pro-inflammatory chemicals called cytokines, or alcohol and cytokines in the laboratory for 24 hours, and then observed changes in gene expression in each condition. They also looked at the impact of alcohol exposure on the cells' ability to phagocytose beta-amyloid.
They found that gene expression was altered for 312 genes under alcohol conditions; for 3,082 for the proinflammatory condition and 3,552 for alcohol and the proinflammatory condition. Changes in gene expression – either an increase or decrease in expression compared to normal levels – averaged about 16% and ranged from a 50% decrease to a 72% increase. Only a handful of genes were involved in both phagocytosis and inflammation.
“Among the genes we saw altered were many involved in phagocytosis, and this is the first time this has been demonstrated,” Feinstein said. “While these studies were conducted in isolated cells, our findings suggest that alcohol impairs the ability of microglia to keep the brain free of amyloid beta and may contribute to the development of Alzheimer's disease.”
After the researchers exposed the cells to levels of alcohol at doses comparable to those found in humans after binge drinking or heavy drinkers, they found that microglial phagocytosis was significantly suppressed by about 15 percent after one hour .
“We did not continue the study to see whether phagocytosis was further impaired after prolonged exposures to alcohol,” Feinstein said, “but it appears that these changes in microglial cells could be a contributing factor to the development of AD. Alzheimer's“.
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