Gene discovery may explain why more women get Alzheimer's disease

In order to understand why more women than men are diagnosed with the illness, researchers have discovered a gene that appears to raise the risk of Alzheimer's in females.

O6-Methylguanine-DNA-Methyltransferase, often known as MGMT, is a key player in how both men and women's bodies repair DNA damage. However, no link between MGMT and Alzheimer's disease in males was discovered by researchers.

According to senior research coauthor Lindsay Farrer, head of biological genetics at Boston University School of Medicine, "it's a female-specific finding—possibly one of the strongest connections of a genetic risk factor for Alzheimer's in women."

According to the Alzheimer's Association, women make up two-thirds of the 6.5 million Americans who are now suffering from the fatal brain illness. This pattern is prevalent all throughout the world.

According to Dr. Richard Isaacson, director of the Alzheimer's Prevention Clinic at Florida Atlantic University's Schmidt College of Medicine, who was not involved in the study, "women may be in the fast-lane toward the disease due to unique genetic risk factors like APOE 4 and MGMT, and sex-specific risk factors like the sudden reduction in estrogen during the peri-menopause transition, while men are sitting in traffic."

According to Isaacson, the APOE 4 gene is thought to be the biggest risk factor for the eventual onset of Alzheimer's in those over 65. This is "particularly true for women, who are more affected by APOE 4 than males," he added.

Nevertheless, while some women without the gene may still have Alzheimer's, many women with APOE 4 don't.

Further research is required, according to Isaacson. "Perhaps MGMT is a critical missing piece of the risk prediction puzzle for these women," he added.

a fortunate finding

The presence of the novel gene was discovered in two different populations of humans. A group of Hutterian Brethren women who live communally in the countryside of South Dakota and Montana were being studied by researchers from the University of Chicago who were examining their genetic composition. Hutterites are a good candidate for genetic study since they are a closed group that intermarries amongst themselves and maintains detailed genealogical records.

According to senior research coauthor Carole Ober, chair of human genetics at the University of Chicago, "the relatively homogeneous environment and less genetic variation in Hutterites boosts our capacity to identify connections in smaller sample numbers than necessary for studies in the broader population."

Ober contacted Boston's Farrer to see if he could assist reproduce her findings when the new relationship with MGMT surfaced in her investigation.

Farrer was taken aback by the call because she was in the middle of a sizable genetic analysis of more than 10,000 women from the Alzheimer's Disease Genetics Consortium research.

I informed her that our investigation had revealed the exact same gene, Farrer added. "Two separate investigations that were initiated independently of one another identify the same gene through serendipity, which to me lends a great deal of confidence that the finding is robust."

In Alzheimer's Disease & Dementia: The Journal of the Alzheimer's Association, the combined study was released on Thursday.

a danger signal for females without APOE 4

The study team excluded any link between the MGMT gene and Alzheimer's disease in males by comparing the results to autopsied male brain tissue.

Researchers discovered that MGMT expression in women was significantly associated with the development of beta amyloid and tau, two proteins that are hallmarks of Alzheimer's disease, when they examined MGMT via epigenetics, which is what happens when a gene is switched on or off by behaviors and environmental factors.

The relationship between MGMT and tau tangles and amyloid plaques was "particularly evident in women who don't have APOE 4," according to Farrer.

The main job of APOE, which is regarded as an important protein, is to "transport cholesterol around in your body, and without that you'd be in danger," according to Farrer. However, research suggests that the APOE 4 variant may deposit more fatty acid accumulation than the other APOE family members, prompting researchers to speculate that there is a cholesterol link to Alzheimer's disease.

In fact, a research by Farrer indicated having high blood sugar and cholesterol in your 30s may increase your risk for Alzheimer's disease decades later. The study was published in March.

"The process to developing Alzheimer's disease is complex. APOE 4 is a component of the lipid, or cholesterol, pathway, which is now fairly well documented in Alzheimer's "said Farrer.

"The inflammatory route is another one that all chronic diseases share. We might be investigating a different DNA repair route with MGMT, or MGMT could be involved in one of these other pathways but we don't yet know how "Added Farrer.

Individualized medicine

Experts encourage women to engage with their doctors to try to determine which route they may be on.

In addition to advocating for a brain-healthy lifestyle that includes regular exercise, a Mediterranean-style diet, enough sleep, and stress-reduction strategies, Isaacson said interventions might include maintaining good blood pressure, cholesterol, and blood sugar levels.

According to Dr. Kellyann Niotis, a neurologist at the Alzheimer's Prevention Clinic at Weill Cornell Treatment and NewYork-Presbyterian who was not involved with the study, scientists will soon be able to provide more tailored medicine to women.

In the near future, Niotis said, "we will be able to provide women at risk more sophisticated evaluations, such thorough genetic testing in a clinic environment, to more accurately estimate their risk and create tailored risk-reduction strategies for the best possible brain protection."