Alzheimer’s: Influence of Epigenetic Changes Demonstrable

From environmental factors to therapeutic targets: How recent studies are expanding the understanding and treatment of Alzheimer’s disease

In 2020, a significant step in dementia research marked a turning point: the “Committee on Dementia Prevention” of the prestigious journal The Lancet Neurology added a critical factor – air pollution – to the list of modifiable risk factors that could help prevent dementia.

This addition was based on the finding that particulate pollutants in the air accelerate the development of neurodegenerative processes. These include diseases that impair blood flow to the brain and heart, as well as the formation of Alzheimer’s-specific plaques by amyloid beta proteins and their precursors. In particular, high concentrations of nitrogen dioxide, particulate matter from traffic exhaust and wood burning in private households have been linked to an increased risk of dementia.

But the danger is not only lurking in the air. A variety of other environmental contaminants, including pesticides, metals, mold toxins, microplastics, mineral oils and industrial additives such as plasticizers, are also among the factors that can increase the risk of Alzheimer’s disease. Even stimulants such as alcohol and tobacco, as well as certain medications – for example anticholinergics, which are prescribed for a wide range of indications – are suspected of contributing to an increase in the risk of Alzheimer’s disease.

Earlier studies had already shown that numerous genes whose mutations increase the risk of Alzheimer’s are located in the immune system. However, the focus of research was mainly on the central immune system in the brain, as Alzheimer’s is considered a disease of the brain. The immune system in the blood, also known as the peripheral immune system, has been largely ignored.

Epigenetic changes in the blood immune system of Alzheimer’s patients uncovered

A new study from Northwestern University in Illinois has made a significant breakthrough in Alzheimer’s research: it has uncovered epigenetic changes in the blood immune system of Alzheimer’s patients. This discovery suggests that environmental and behavioral factors may play a role in the risk of developing Alzheimer’s disease. Interestingly, the results show that these epigenetic adaptations affect genes that are crucial for susceptibility to Alzheimer’s disease. This could be caused by external influences such as viral infections or environmental pollutants.

The research team, led by David Gate, assistant professor of neurology at Northwestern University’s Feinberg School of Medicine, speculated that these changes could possibly be triggered by previous viral infections, exposure to environmental pollutants or by various lifestyle factors and behaviors. In their study, they found that immune cell type in Alzheimer’s patients shows traces of epigenetic changes.

This innovative finding opens up new avenues for treatment by offering the possibility of targeting specific genes. It also emphasizes the critical importance of the peripheral immune system in the fight against Alzheimer’s disease and offers a new starting point for understanding and potentially halting its progression. “It is possible that these findings link the peripheral immune response to Alzheimer’s risk,” says David Gate. “We have not yet clarified whether these changes reflect brain pathology or whether they trigger the disease.”

Epigenetic changes characterized by open chromatin

He and his research team have found that epigenetic changes characterized by the presence of open chromatin occur in the immune cells of Alzheimer’s patients. Chromatin, which packages the DNA in cells when exposed, makes the cell’s genome more susceptible to alterations. Upon further investigation, Gate specifically identified that in these immune cells, a receptor called CXCR3 is more highly exposed on the T cells. He believes that CXCR3 acts as an antenna for T cells, allowing them to enter the brain, although T cells do not normally enter the brain because they could trigger inflammation there.

According to Gate, the brain sends out a signal when it is damaged, and the T cells are guided to this signal by their “antenna” CXCR3. The presence of T cells in the brain can be potentially harmful, but it is unclear whether these cells could also perform reparative functions in the brain. In addition, epigenetic changes in inflammatory proteins in white blood cells, particularly monocytes, have been discovered.

The research results provide the following summarized findings: Epigenetic modifications in the immune cells of the blood of Alzheimer’s patients could be due to environmental influences and thus affect genes that play a role in Alzheimer’s risk. The results underline the important role of the peripheral immune system in Alzheimer’s disease, whereby T cells may become active in response to signals of brain damage. In addition, this study opens up the possibility of identifying potential targets for therapeutic approaches within the peripheral immune system, offering new treatment options for Alzheimer’s disease.

Immune function probably significantly altered in Alzheimer’s patients

The researchers also made another important discovery: epigenetic modifications in the inflammatory proteins of white blood cells, especially monocytes. Gate interprets the findings to mean that immune function is significantly altered in Alzheimer’s patients. He speculates that environmental factors such as pollutants or infections suffered in the course of life could cause these epigenetic changes.

The results of the study also reveal several genes that could serve as potential therapeutic targets for influencing the peripheral immune system. The next steps in the research will be preclinical studies using in vitro culture systems and animal models to test the efficacy of these target genes.

The study was published in “Neuron” on February 9, 2024: