A gene has been identified which could play a role in increasing the risk of women developing Alzheimer's disease.
Alzheimer's disease is the number one cause of dementia worldwide, and women are more affected than men, though there has been little understanding of why up until now. This progressive neurodegenerative disorder leads to the loss of neurons within the brain associated with memory, primarily affecting those over the age of 65. The allele apolipoprotein E (APOE) ε4, a variant of the APOE gene, has been previously determined as a dominant risk factor for developing Alzheimer's. Around 60 percent of people with European ancestry carry the (APOE) ε4 allele, while only one in four of the global population does. This suggests that the APOE gene cannot be the only contributing risk factor for developing Alzheimer's.
The study, published in the journal of Alzheimer's Disease & Dementia: The Journal of the Alzheimer's Association, was carried out by researchers from the University of Chicago, Illinois, and Boston University School of Medicine, Massachusetts.
They carried out a meta-analysis of genome-wide association studies (GWAS) to identify genome-wide associations with developing Alzheimer's. First the researchers looked at a cohort made up of Hutterites, including individuals who had developed Alzheimer's and controls who had not over the age of 85.
Hutterites are descended from a relatively small number of ancestors and exhibit a founder's effect. This flagged the O6-methylguanine-DNA methyltransferase (MGMT) gene locus as linked to Alzheimer's disease risk. Researchers then looked at another cohort of 10,304 women without the APOE ε4 allele, including 3399 Alzheimer's disease cases and 6905 control samples and reproduced this result in the second cohort.
Further analysis showed that epigenetically-regulated gene expression of MGMT, a gene known to have a role in repairing DNA damage, is significantly associated with the creation of two proteins that accumulate in the brains of Alzheimer's patients amyloid-β and tau.
'…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 allele, the Hutterite sample was too small to evaluate this pattern with any certainty,' said Dr Farrer.
In future, researchers will focus on determining why MGMT is a risk factor for women and not men.