Alzheimer’s DNA Methylation Study Uncovers 84 New Genes Associated with the Disease

Alzheimer: Phosphorylation of Tau proteins leads to disintegration of microtubuli in a neuron axon
[Source: selvanegra/Getty Images]

A study examining DNA methylation patterns revealed new insights into epigenetic gene regulation in dementia. In the process, the analysis led to discovery of 84 genes which were not previously known to have an association with Alzheimer’s disease (AD).

“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,” the authors from the University of Exeter in the U.K. write in their paper published in Nature Communications.

The analysis focused on methylation changes associated with neurofibrillary tangles, known as Braak changes, given that these tangles are a classic hallmark of Alzheimer’s dementia.

This meta-analysis, believed to be the largest of its type, reviewed six earlier DNA methylation studies of AD, which represented brain tissue studies of 1,453 individuals. They observed different epigenetic patterns of Braak DNA methylation changes in different cortical brain regions and the cerebellum. People with severe AD had noticeably different levels of DNA methylation levels in the prefrontal cortex, but not in the cerebellum.

“By performing a meta-analysis within each tissue, we have been able to identify 236, 95 and ten significant differentially methylated positions in the prefrontal cortex, temporal gyrus and entorhinal cortex, respectively,” they write.

Focusing just on the cortex, which included an analysis of 1,408 donors, the team identified 220 hot spots in the genome linked to 121 genes. Of these, 84 genes were previously unknown to have a significant association with AD. Fifteen genes of those 84 genes were found to be completely novel regarding their relationship with the disease.

They then correlated those patterns with the amount of neurofibrillary tangles within the brain. Half of the original 220 sites, or 110, could distinguish whether a brain sample had high or low levels of disease, with more than 70 per cent accuracy.

Professor Katie Lunnon, of the University of Exeter, who led the research, said: “Our study is the largest of its kind, giving important insights into genomic areas that could one day provide the key to new treatments. 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”

Looking ahead, the team raises the possibility of studying whether amyloid-beta, another neuropathological hallmark of AD, is associated with differentially methylated regions of brain tissues.

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