Researchers have identified new variants in the MGMT gene that increase an individual’s chance of developing Alzheimer’s disease, but only in women
Alzheimer’s disease is the most common form of dementia, and it affects more women than men.
Variants in the APOE gene are among the most-studied risk factors for developing the condition. One version of APOE, called the APOE epsilon 4 allele, has the largest effect of any genetic variant yet discovered on an individual’s chance of developing Alzheimer’s; about 40% of people who develop the disease have this variant, leaving 60% with a differing pathology.
A new study published in Alzheimer’s Disease & Dementia shows that, in women, variants in a gene called MGMT – an important part of our cell’s DNA repair systems – may be implicated.
Two datasets pinpoint MGMT
In the study, the researchers were able to find a connection between MGMT variants and Alzheimer’s disease by looking at two different datasets.
In the first dataset, they looked at genomes from an extended family of Hutterites where all those who developed dementia were women. The Hutterites migrated from central Europe to the USA in the 16th century. This population tend to marry within their own community, and so their comparatively small gene pool has proven helpful in genomic research.
“The relatively uniform environment and reduced genetic variation in Hutterites increases our power to find associations in smaller sample sizes than required for studies in the general population,” explained lead author Professor Carole Ober, University of Chicago’s head of human genetics.
The second dataset was a broader group of more than 10,000 women who do not have the APOE epsilon 4 allele. These women were part of a separate investigation that looked for links between breast cancer and dementia.
Both datasets identified an association between Alzheimer’s and MGMT variants.
The impact of MGMT
Some variants in the MGMT gene mean it is ‘hidden’ from the cell. These variants can be due to the MGMT DNA itself, which stops it being read, or so-called epigenetic modifications that are modifications that go ‘on top of’ the DNA. An example is DNA methylation, where the cell attaches methyl groups onto sections of DNA to alter (normally hide) a gene’s availability.
After finding the association between MGMT and Alzheimer’s, the researchers compared data on gene expression, DNA methylation, and cellular hallmarks of Alzheimer’s disease in brain tissue samples. They discovered that variants of MGMT, which are preventing the cell ‘reading’ the gene, have a strong connection to the development of tau and amyloid-beta proteins. These proteins build up into plaques in brain cells, disrupting cellular activity and leading to the cognitive decline that Alzheimer’s disease is known for.
- Further learning: What is epigenetics?
Why only women?
Women and men can have different genetic risk factors. In this case, DNA methylation at the MGMT gene was more pronounced in woman, leading to its MGMT protein not being made.
“This is one of a few, and perhaps the strongest, associations of a genetic risk factor for Alzheimer’s that is specific to women,” said senior author Professor Lindsay Farrer, Boston University School of Medicine’s chief of biomedical genetics. “This finding is particularly robust because it was discovered independently in two distinct populations using different approaches.”
The research shows the importance of looking for genetic risk factors that may more heavily affect one sex over the other. Such risk factors could be missed in studies using large, mixed datasets.