Epigenetic Control of MGMT Variants Correlated with Alzheimer Disease in Women 

In a study published in Alzheimer’s Disease & Dementia, researchers found that methylguanine methyltransferase (MGMT) gene variants correlated with increased incidence of Alzheimer disease (AD) in 2 populations of women. MGMT is a DNA repair-associated protein. In this study, individuals were identified as women via genotyping and self-identification.  

In both the national Alzheimer's Disease Genetics Consortium of analysis of data from 10,340 women showed those with the rs12775171 MGMT variant had a 40% higher likelihood of AD (odds ratio [OR]=1.4, P<.001). Women in this dataset were negative for the presence of apolipoprotein E epsilon 4 allele (ApoE ε4), which is a known risk factor for AD. Among 22 women from a Hutterite founder group with a limited gene pool, those with the MGMT rs12256016 and rs2803456 variants had a twofold increased likelihood of AD (OR=2.0; P<.001).

“This is one of a few and perhaps the strongest associations of a genetic risk factor for AD that is specific to women,” said Lindsay Farrer, PhD, chief of biomedical genetics, Boston University School of Medicine. “This finding is particularly robust because it was discovered independently in 2 distinct populations using different approaches. While the finding in the large dataset was most pronounced in women who don’t have APOE ε4, the Hutterite sample was too small to evaluate this pattern with any certainty.”

Evaluation of amyloid β levels in the brain, single nucleotide polymorphisms (SNPs), and MGMT methylation showed and association of a single MGMT locus and risk of AD.  MGMT gene expression, regulated by methylation of MGMT, was also associated with AD-related neuropathology in the brain. These data suggest that epigenetic control of MGMT expression through DNA methylation of specific variants plays a role in the association with AD.

Although the drivers of DNA methylation are still being elucidated, environmental and lifestyle factors (eg, smoking and alcohol) and biologic factors (eg, age and sex) are associated with DNA methylation, further supporting these as potential targets for disease modification.