Study Explores Alzheimer’s Impact on Non-Neuronal Brain Cells

DNA methylation research out of the United Kingdom’s University of Exeter has found that brain cells other than neurons die off as Alzheimer’s disease progresses and also identified previously unknown genes that play a role in dementia and could become targets for drug development.

DNA methylation—the process by which the activity of genes is regulated—is increasingly thought to play a key role in the development of diseases such as dementia. So far, research on DNA methylation in the brain has only been able to look at “bulk” samples of post-mortem tissue. In other words, scientists have been limited to looking at average levels of DNA methylations across all the different cell types in a piece of brain tissue. Now, the Exeter team has developed a technique to purify the cell populations, meaning they can see DNA methylation activity in each distinct cell type for the first time.

“Our study has enabled us to explore the changes associated with the development of dementia across individual populations of cells. It’s often assumed that these changes primarily occur in neurons, but surprisingly we found much more dramatic shifts in non-neuronal cell-types. This means we can start to understand more about the mechanisms involved in disease and identify pathways that might be targetable by novel drugs,” says Jonathan Mill, Professor of Epigenomics at the University of Exeter Medical School.

The research utilized 631 brain samples donated to the Brains for Dementia Research cohort, which included people who died with Alzheimer’s disease.  From each person, the team dissected two distinct regions of the cortex that are affected differently in Alzheimer’s disease. Each donor had very comprehensive measures of the pathology of the brain taken at post-mortem, providing the team with very detailed information about the progression of the disease.

 “Our study highlights the power of using multiple measures of neuropathology to identify epigenetic signatures of Alzheimer’s disease, as well as the importance of looking at the activity of different types of cell, and when and how they are activated in disease,” Mill adds. “The generosity of the people who donated their brains for research has allowed us to make these exciting discoveries and could hold the key to finding new treatments for Alzheimer’s disease.”

Dr. Richard Oakley, Associate Director of Research at Alzheimer's Society, which co-funded the study and supports Brains for Dementia Research, said further research will enable researchers to pinpoint exactly what is going wrong inside brain cells to cause dementia and inform how to develop “desperately needed” new targeted treatments for diseases that cause dementia.

The paper, entitled “DNA methylation signatures of Alzheimer’s disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types,” was published recently in Nature Communications.