Gene Linked with Alzheimer’s Disease Risk in Women

U.S. researchers have identified a new gene that may increase the risk of Alzheimer’s disease in women.

Their study indicated that variants in the MGMT gene were associated with Alzheimer’s disease, particularly in women lacking the apolipoprotein E (APOE) ɛ4 allele.

The researchers believe that the expression of MGMT contributes to the development of two hallmark proteins involved in Alzheimer’s disease, amyloid beta and tau, particularly in women.

Their findings are published in Alzheimer’s Disease & Dementia: The Journal of the Alzheimer’s Association.

“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 Lindsay Farrer, PhD, chief of biomedical genetics at Boston University School of Medicine.

“This finding is particularly robust because it was discovered independently in two distinct populations using different approaches.”

The team conducted two complementary genome-wide association studies (GWAS). The first involved Hutterites, a founder population of central European ancestry, while the second was from a dataset chosen due to previous evidence linking Alzheimer’s disease with breast cancer.

The APOE ε4 allele is the most established and strongest genetic risk factor for the Alzheimer’s disease occurring after age 65, the authors point out. However, only  approximate 40 per cent of sufferers carry this allele compared with around 13.7 per cent of the population, implying that other genes contribute to this disease.

Noting previously reported genetic associations between Alzheimer’s disease and single nucleotide polymorphisms in the MAPT region among women lacking the APOE ε4 allele, they studied the genomes of a subset of women in the Alzheimer’s Disease Genetics Consortium (ADGC).

Specifically, they studied 10,304 women lacking the APOE ε4 allele (ε4–), which included 3399 AD cases and 6905 control subjects from 30 GWAS datasets assembled by ADGC.

DNA and genotypes for five women among 29 cases of Alzheimer’s disease in a larger Hutterite kindred were also compared with 26 control individuals with no reported dementia by the age of 85 years, for whom genetic information was available.

Farrer and co-workers identified a novel association between Alzheimer’s disease and genetic variants in MGMT among women lacking the APOE ε4 allele in the ADGC cohorts (rs12775171, odds ratio [OR] = 1.4).

They also found an association between Alzheimer’s disease and genetic variants within and upstream of MGMT in Hutterite women regardless of APOE ε4 carrier status (rs12256016 and rs2803456, OR = 2.0).

The researchers believes: “Future research should also focus on mechanisms that explain the stronger [Alzheimer’s Disease]/MGMT association among women who lack APOE ɛ4 to understand more precisely the mechanism underlying the role of MGMT in [Alzheimer’s Disease] and provide insight into potential novel therapeutic approaches.”