New Dementia Insights from a Brain Epigenetics Study

A group of scientists led by the University of Exeter has discovered 84 new genes connected to dementia, revealing fresh insights into how genes are regulated in the condition.

In a publication published in Nature Communications titled "A meta-analysis of epigenome-wide association studies in Alzheimer's disease highlights novel differentially methylated sites across cortex," the team pooled and evaluated data from over 1,400 people from six separate research. Brain tissues from persons who had died of Alzheimer's disease were used in these investigations.

“Although previous studies were limited in sample size and used different brain areas, epigenome-wide association studies of Alzheimer's disease have highlighted neuropathology-associated DNA methylation variations. We used data from six Alzheimer's disease DNA methylomic investigations (N = 1453 unique individuals) to find differential methylation linked with Braak stage in different brain regions and across cortex. At Bonferroni significance, we find 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus, and 10 CpGs in the entorhinal cortex, with none in the cerebellum,” the researchers write.

“Our cross-cortex meta-analysis (N = 1408 donors) uncovers 220 CpGs linked to neuropathology, assigned to 121 genes, 84 of which have never been reported at this significance threshold. We confirmed our findings with two more DNA methylomic datasets with over 600 distinct donors. The summary statistics from the meta-analysis can be found in our online data resource.”

The study looked at DNA methylation at nearly half a million places in the genome and was financed by the Alzheimer's Society and supported by the Medical Research Council and the National Institutes of Health. Such epigenetic changes, unlike genes, can be affected by environmental circumstances, making them theoretically reversible and a potential avenue to new treatments.

The research looked at epigenetic patterns across the genome in a variety of brain areas. The researchers then linked the quantity of DNA methylation to the quantity of neurofibrillary tangles in the brain, which is a key indicator of Alzheimer's disease severity.

Before looking for common abnormalities across these cortical regions, the team looked at distinct regions of the brain that are impacted in Alzheimer's disease. They discovered 220 novel genes and 220 new locations in the genome that revealed different amounts of DNA methylation in the cortex in those with more severe Alzheimer's disease than in the cerebellum.

The researchers went on to show that a subset of 110 of these locations could accurately determine whether a brain sample had high or low levels of illness in two separate datasets. This shows that in Alzheimer's disease, epigenetic alterations in the brain are extremely constant. The findings were later verified in an independent group of brain samples from the Alzheimer's Society and Alzheimer's Research UK-funded Brains for Dementia Research cohort.

Katie Lunnon, PhD, professor of dementia genomics at the University of Exeter, said, "Our study is the largest of its kind, providing crucial insights into genomic areas that could one day give the key to new treatments." “The next stage in our research will be to see if these epigenetic alterations result in quantifiable alterations in gene and protein expression levels. This will allow us to see if existing medications that are known to change the expression levels of these genes and proteins might be repurposed to effectively treat dementia.”

A number of researchers from the United States (Columbia University and Mount Sinai School of Medicine in New York, Rush University Center in Chicago, and Arizona State University) and Europe were also participating in the study (Maastricht University in Netherlands, University of Saardland, Germany).