Immune genes are altered in the blood of Alzheimer’s patients

A new study from Northwestern Medicine has found that the immune system in the blood of Alzheimer’s patients is epigenetically altered. This means that patients’ behavior or environment has caused changes that affect how their genes work.

Many of these altered immune genes are the same ones that increase the risk of developing Alzheimer’s disease. Northwest scientists believe the cause could be a previous viral infection, environmental pollutants or other lifestyle factors and behaviors.

“It is possible that these findings implicate the peripheral immune response in Alzheimer’s disease risk,” said principal investigator David Gate, an assistant professor of neurology at Northwestern University’s Feinberg School of Medicine. “We don’t yet know whether these changes reflect brain pathology or whether they precipitate disease.”

The study was published on February 9 in Neuron.

Previous research has shown that many of the mutated genes putting a person at higher risk of developing Alzheimer’s disease are found in the immune system. But scientists have primarily studied the brain’s central immune system, because Alzheimer’s disease is a brain disease. They have largely ignored the immune system found in the blood, also known as the peripheral immune system.

Gate decided to study blood. He and his colleagues found that each type of immune cell in Alzheimer’s patients showed epigenetic changes, indicated by open chromatin. Chromatin is the packaging of DNA in cells. When chromatin is opened or exposed, the cell genome is vulnerable to alteration.

Next, Gate looked at which genes are most open in these immune cells. He found that a receptor, CXCR3, present on T cells, was more exposed. Gate believes CXCR3 functions like an antenna on T cells that allows the cells to enter the brain. T cells do not normally enter the brain because they can cause inflammation.

“The brain sends out a signal that it’s damaged, and the T cells go to that signal through their antenna, CXCR3,” Gate said.

“T cells can be very toxic in the brain, but we also don’t know whether these cells could attempt to repair damage to the brain,” Gate said.

Gate also discovered epigenetic changes in inflammatory proteins in white blood cells called monocytes.

“Overall, these results indicate that the immune function of patients with Alzheimer’s disease is significantly impaired,” Gate said. “It could be that environmental factors, such as pollutants or infections that a person has acquired during their life, are causing these epigenetic changes.”

The results revealed several genes that could be therapeutic targets to manipulate the peripheral immune system. The next steps in research consist of preclinical studies using in vitro culture systems and animal models to test these targets.

Other Northwest authors include Abhirami Ramakrishnan, Natalie Piehl, Brooke Simonton, Milan Parikh, Ziyang Zhang, Victoria Teregulova and Lynn van Olst.

The title of the article is “Epigenetic dysregulation in peripheral immunity in Alzheimer’s disease.”