Epigenetic Changes in Immune Cells Linked to Alzheimer’s Disease

Alzheimer’s disease is a degenerative brain disorder that impacts millions globally. While the exact cause of the disease is still unknown, a recent study by Northwestern University (NU) has shed light on the potential role of epigenetic modifications in the immune system of Alzheimer’s patients.

The study found that Alzheimer’s patients experience epigenetic changes in their blood’s immune system, which could be influenced by environmental factors, past infections, and lifestyle behaviors. These findings could pave the way for the development of new therapeutic targets for modulating the peripheral immune system and potentially delaying the onset or reversing the damage caused by the disease.

Many of these altered immune genes coincide with those known to increase the risk of Alzheimer’s disease. Scientists at NU speculate that these changes could be triggered by past viral infections, exposure to environmental pollutants, or other lifestyle factors and behaviors.

Lead investigator David Gate, an assistant professor of neurology at NU’s Feinberg School of Medicine, shares insights into the study’s implications: “Our findings suggest a possible connection between the peripheral immune response and Alzheimer’s disease risk. Further exploration is needed to determine whether these changes reflect brain pathology or contribute to disease progression.”

In previous blog posts, we have discussed how scientists are exploring epigenetics to better understand the development of Alzheimer’s disease. Epigenetic marks like DNA methylation and certain histone modifications found in the blood and brain have been previously linked to Alzheimer’s disease. 

Published in the journal Neuron, the current study builds upon previous research indicating that many of the mutated genes associated with higher Alzheimer’s risk are related to the immune system. However, past studies mainly focused on the central immune system in the brain, given that Alzheimer’s is primarily considered a brain disease, overlooking the peripheral immune system present in the blood.

Gate’s team decided to investigate the blood’s immune system using single-cell sequencing techniques to study epigenetic and transcriptional changes in the peripheral immune system of Alzheimer’s patients.

What they found was that every type of immune cell in the patients exhibited epigenetic changes, as indicated by open chromatin—a state where the DNA packaging within cells is exposed, rendering the genome susceptible to alterations.

Further analysis revealed that a receptor called CXCR3 on T-cells, which are a type of white blood cell crucial for immune response, was particularly exposed. Gate suggests that CXCR3 functions as an antenna on T-cells, enabling them to enter the brain.

T-cells typically do not enter the brain because they can trigger inflammation. However, Gate proposes that these cells might respond to signals of brain damage, possibly attempting to repair the damage.

Additionally, Gate identified epigenetic changes in inflammatory proteins in white blood cells known as monocytes.

Overall, these findings suggest significant alterations in immune function among Alzheimer’s patients, possibly influenced by the environment or past infections. As Gate expressed, “It could be that environmental factors, like pollutants, or infections that a person has in their lifetime cause these epigenetic changes.”

The study highlights several genes that could serve as therapeutic targets for modulating the peripheral immune system. Future research will encompass preclinical investigations utilizing in vitro culture systems and animal models to assess the efficacy of these targets. The results of this study not only bring attention to potential therapeutic targets but also provide new insights into the intricate relationship between epigenetics, genetic risk factors, and peripheral immunity in Alzheimer’s disease.

Source: A. Ramakrishnan, et al. Epigenetic dysregulation in Alzheimer’s disease peripheral immunity. Neuron, February 9, 2024.

Reference: Immune genes are altered in Alzheimer’s patients’ blood, Northwestern University. February 9, 2024.