A new study by Northwestern Medicine has found that the immune system in the blood of Alzheimer’s patients is epigenetically changed. This means that the behavior or environment of the patients has caused changes that affect the functioning of their genes.
Many of these altered immune genes are the same ones that increase a person’s risk of Alzheimer’s. Scientists from Northwestern suspect that the cause could be a previous viral infection, environmental pollutants, or other lifestyle factors and behaviors.
„It is possible that these findings have an impact on the peripheral immune response in Alzheimer’s risk. We have not yet determined whether these changes reflect brain pathology or trigger the disease.“
David Gate, Lead Investigator, Assistant Professor of Neurology at the Feinberg School of Medicine, Northwestern University.
The study was published on February 9th in Neuron.
Past research has shown that many of the mutated genes that increase the risk of Alzheimer’s are in the immune system. However, scientists have mainly focused on the central immune system in the brain, as Alzheimer’s is a brain disease. They have largely ignored the immune system in the blood, also known as the peripheral immune system.
Gate decided to examine the blood. He and colleagues discovered that every type of immune cell in Alzheimer’s patients has epigenetic changes revealed by open chromatin. Chromatin is the packaging of DNA in cells. When chromatin is open, or exposed, the genome of the cells is susceptible to changes.
Gate then examined which genes in these immune cells are more open. He found that a receptor – CXCR3 – on the T-cells was more exposed. Gate believes that CXCR3 functions like an antenna on T-cells, allowing the cells to penetrate into the brain. T-cells do not normally enter the brain because they can cause inflammation.
„The brain sends out a signal that it is damaged, and the T-cells follow that signal with their CXCR3 antenna,“ Gate said.
„T-cells can be very toxic in the brain, but we also don’t know if these cells might be trying to repair the damage in the brain,“ Gate said.
Gate also discovered epigenetic changes in inflammatory proteins in white blood cells known as monocytes.
„Overall, these results suggest that immune function in Alzheimer’s patients is significantly altered,“ Gate said. „It’s possible that environmental factors such as pollutants or infections a person has throughout their life are causing these epigenetic changes.“
The results revealed several genes that could be therapeutic targets for manipulating the peripheral immune system. The next research steps are preclinical studies using in vitro culture systems and animal models to test these targets.
Other authors from Northwestern 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 of Alzheimer’s Disease.“
The research is supported by the National Institute of Neurological Disorders and Stroke Grant NS112458, the National Institute on Aging Grant AG078713, both from the National Institutes of Health, the Bright Focus Foundation, the Alzheimer’s Association, and the Cure Alzheimer’s Fund.
Ramakrishnan, A., et al. (2024) Epigenetic Dysregulation in Peripheral Immunity of Alzheimer’s Disease. Neuron. doi.org/10.1016/j.neuron.2024.01.013.