A team of US researchers have uncovered a new gene – known as MGMT – that may increase the risk of Alzheimer’s disease in women.
In a study performed by experts from the University of Chicago and Boston University School of Medicine (BUSM), researchers have identified a novel gene that may be instrumental in the development of Alzheimer’s disease. The MGMT discovery may enable scientists to design new interventions to safeguard women from the neurodegenerative condition.
The study’s results are published in Alzheimer’s Disease & Dementia: The Journal of the Alzheimer’s Association.
The role of genetics in Alzheimer’s development
Alzheimer’s disease is the predominant cause of dementia, and in the US alone, the progressive neurodegenerative disorder affects over 5.8 million people. Researchers have discovered various genetic variants that increase the risk of developing Alzheimer’s, with the most notable being APOE ε4, which is prevalent in people over 65.
Estimates suggest that around 60% of people of European ancestry with Alzheimer’s carry APOE ε4, whereas only 26% of the general population carry the genetic variant, suggesting that other genes are influential in the disease’s development.
The cause of Alzheimer’s disease in women
For their investigation, the team performed a genome-wide association study (GWAS) analysing two independent datasets using two different methods. The first examined dementia in a large extended family of Hutterites, which is a founder population of central European ancestry often studied for genetic determinants of disease due to their relatively small gene pool. All of the individuals with Alzheimer’s disease in this study were women.
The second study examined the genetic data from a cohort of 10,340 women who did not have the APOE ε4 gene, with both datasets suggesting that MGMT plays a role in the development of Alzheimer’s disease in women.
Lindsay Farrer, PhD, the chief of biomedical genetics at BUSM and a senior author of the study, said: “This is one of a few and perhaps the strongest associations of a genetic risk factor for Alzheimer’s that is specific to women. This finding is particularly robust because it was discovered independently in two 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.”
Subsequently, the team employed several types of genetic data to analyse MGMT further and a range of other Alzheimer’s disease genetic traits from human brain tissues. This illuminated that epigenetically regulated gene expression of MGMT – one of the ways cells control gene activity without modifying the DNA sequence and has a role in repairing DNA damage – was linked to amyloid-β and tau, two Alzheimer’s disease proteins, especially among women.
Carole Ober, PhD, Chair of Human Genetics at UChicago and a senior author of the study, commented: “This study highlighted the value of founder populations for genetic mapping studies of diseases like Alzheimer’s. The relatively uniform environment and reduced genetic variation in Hutterites increase our power to find associations in smaller sample sizes than required for studies in the general population. The validation of our findings in the larger dataset used by the Boston University group was enormously gratifying and ultimately led to supportive epigenetic mechanisms that connected both sets of GWAS results to the MGMT gene.”
The team is now aiming to conduct further studies to investigate how MGMT increases the risk of Alzheimer’s disease in women compared to men.
