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Epigenetic changes in blood immune cells suggest that viral infections and other external factors may play a role in Alzheimer’s risk. Image credit: Kilito Chan/Getty Images.
  • Scientists are continuing to look for new ways to treat Alzheimer’s disease as rates are expected to increase.
  • Researchers from Northwestern University Feinberg School of Medicine found that immune cells in the blood of people with Alzheimer’s disease are epigenetically altered.
  • The study also discovered several genes that may be therapeutic targets for manipulating the body’s peripheral immune system.

With rates of Alzheimer’s disease expected to rise and still no cure for this type of dementia, finding new ways to treat this disease has been at the forefront of research over the past few years.

Adding to this research is a new study from Northwestern University Feinberg School of Medicine. The findings recently published in the journal Neuron found that immune cells in the blood of people with Alzheimer’s disease are epigenetically altered.

This alteration, the researchers say, is potentially caused by a previous viral infection, environmental pollutants, or other lifestyle factors.

The research revealed several genes that may be therapeutic targets for manipulating the body’s peripheral immune system.

The body’s immune system can be considered as comprising two parts — the central immune system and the peripheral immune system, a term used to describe immune responses that happen outside the brain.

The peripheral immune system includes circulating white blood cells that detect antigens, such as bacteria or viruses, when they enter the body. This part of the immune system acts as the first wave of attack against any foreign substance.

According to Dr. David Gate, assistant professor of neurology at Northwestern University Feinberg School of Medicine and senior and corresponding author on this study, there is mounting evidence that the peripheral immune system plays a role in Alzheimer’s disease.

“In recent years, we have shown that immune cells of the cerebrospinal fluid — a fluid that flows in and around the brain — are clonally expanded and activated,” Dr. Gate told Medical News Today. “This means that they have previously responded to some type of immune stimulus.”

Previous research has connected the peripheral immune system to neurodegenerative diseases, and studies have shown an association between types of peripheral immune cells and cognition, brain structure, and Alzheimer’s disease pathology.

For this study, Dr. Gate said the team wanted to find out whether there might be epigenetic changes within the immune system of Alzheimer’s disease patients that might promote the trafficking of these changes to the cerebrospinal fluid and the brain.

“Epigenetics essentially reflects changes to our DNA that have occurred in the past,” he explained. “There are many influences on epigenetics, such as the environment, pollutants, viral infections, lifestyle factors, and behaviors. It is possible that these influences work in concert, or in isolation, to promote inflammation that puts one at risk of developing Alzheimer’s disease.”

Dr. Gate and his team examined immune cells from peripheral blood samples taken from people with Alzheimer’s disease. When compared to healthy controls, researchers found that every immune cell type in the participants with Alzheimer’s disease had epigenetic changes indicated by open chromatin.

Additionally, scientists looked for which genes were more open in the immune cells and found more exposure in the protein CXCR3 on T cells.

“Epigenetic changes alter the way our genes are translated into proteins,” Dr. Gate explained. “In this study, we observed an epigenetic change in a gene that encodes the protein CXCR3. CXCR3 is a signal receptor on the surface of immune cells called T cells. This receptor essentially serves as an antenna that we believe allows them to traffic signals put out by the Alzheimer’s brain.”

Researchers also found epigenetic changes in a type of white blood cell called monocytes.

“Monocytes are very important to immune defense. They secrete inflammatory proteins that protect your body in the case of infection. In this study, we found that there are epigenetic changes to genes that encode these inflammatory proteins. This is significant because it could signal that Alzheimer’s disease patients have a more pronounced pro-inflammatory immune system.”

– Dr. David Gate

As epigenetics only provides a snapshot into the past, Dr. Gate said we can only speculate on what might have caused these discovered epigenetic changes.

“However, in the past decade, we have grown to appreciate the fact that viral infections are a risk factor for the development of dementias like Alzheimer’s disease,” he continued.

“While our data do not provide evidence that epigenetic changes in Alzheimer’s disease patients’ immune systems were caused by viral infections, this is certainly a tantalizing possibility. In this scenario, viral infections promote inflammatory responses over the course of one’s life that promote Alzheimer’s disease risk via mechanisms that we do not yet understand,” suggested Dr. Gate.

“Our ultimate goal is to design immune cell therapies for Alzheimer’s disease,” Dr. Gate added. “Using information from this study, we can potentially target the genes that harbor epigenetic changes.”

After reviewing this study, Dr. Manisha Parulekar, chief of the Division of Geriatrics at Hackensack University Medical Center in New Jersey, not involved in the research, told MNT she was not surprised by its results.

“Basically, it reinforces the idea that the patient’s behavior or environment has caused changes that affect the way their genes work,” Dr. Parulekar explained. “Many of these altered immune genes are the very same ones that increase an individual’s risk for Alzheimer’s.”

“Alzheimer’s disease is known to have complex pathophysiology, possibly involving multiple genes in combination [with] lifestyle, environmental, and other risk factors. Reading this new article, I am excited to see more evidence of changes in immune cells with changes in genes that were attributed to Alzheimer’s disease. The advancement in this science will likely have implications in [the] prevention and treatment of Alzheimer’s disease.”

– Dr. Manisha Parulekar

MNT also spoke with Dr. Karen D. Sullivan, a board-certified neuropsychologist, owner of the I CARE FOR YOUR BRAIN program, and Reid Healthcare Transformation Fellow at FirstHealth in Pinehurst, NC, about this study.

Dr. Sullivan said that as we do not know much about the peripheral immune system in Alzheimer’s disease, this study is a novel contribution to our understanding of a very complex, multi-faceted neurodegenerative disease.

“The main question I have is the directionality here,” she continued. “Is the peripheral inflammatory response in Alzheimer’s disease a cause or effect? The best thing I take away is that we may have a new therapeutic target in Alzheimer’s disease: restricting peripheral inflammation.”

“We would need to see these results replicated in larger sample sizes and to more deeply understand their relationships to the functional decline of Alzheimer’s disease,” Dr. Sullivan added.