An international team of scientists led by the University of Exeter reports that it has unveiled new insights into how genes are regulated in dementia, including the discovery of 84 new genes linked to the disease.
The collaboration combined and analyzed data from more than 1,400 people across six different studies in a paper (“A meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex”) published in Nature Communications. These studies had used brain samples from people who had died with Alzheimer’s disease.
“Epigenome-wide association studies of Alzheimer’s disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer’s disease (N = 1453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum,” write the investigators.
“Our cross-cortex meta-analysis (N = 1408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further >600 unique donors. The meta-analysis summary statistics are available in our online data resource.”
The project, funded by Alzheimer’s Society and supported by the Medical Research Council and the NIH, looked at DNA methylation at nearly half a million sites in the genome. Unlike genes, such epigenetic processes can be influenced by environmental factors, making them potentially reversible and a possible route to new treatments.
The study looked at epigenetic patterns across the genome, in a number of different regions of the brain. The team then related the amount of DNA methylation to the amount of neurofibrillary tangles within the brain, which is an important hallmark of the severity of Alzheimer’s disease.
The team explored different regions of the brain, which are affected in Alzheimer’s disease before looking for common changes across these cortical regions. They identified 220 sites in the genome, including 84 new genes, which showed different levels of DNA methylation in the cortex in individuals with more severe Alzheimer’s disease, which weren’t seen in the cerebellum.
The team went on to show that a subset of 110 of these sites could distinguish in two independent datasets whether a brain sample had high or low levels of disease, with more than 70% accuracy. This suggests that epigenetic changes in the brain in Alzheimer’s disease are very consistent. The findings were subsequently confirmed in an independent set of brain samples from the Brains for Dementia Research cohort funded by the Alzheimer’s Society and Alzheimer’s Research UK.
“Our study is the largest of its kind, giving important insights into genomic areas that could one day provide the key to new treatments,” said Katie Lunnon, PhD, professor of dementia genomics at the University of Exeter. “The next step for this work is to explore whether these epigenetic changes lead to measurable changes in the levels of genes and proteins being expressed. This will then allow us to explore whether we could repurpose existing drugs that are known to alter the expression levels of these genes and proteins, to effectively treat dementia”
Other researchers involved in the study included a number from the U.S. (Columbia University and Mount Sinai School of Medicine in New York, Rush University Center in Chicago, Arizona State University), and Europe (Maastricht University in Netherlands, University of Saardland, Germany).