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

Scientists have identified a gene that appears to increase the risk of Alzheimer's in women, providing a potential new clue as to why more women than men are diagnosed with the disease.

The gene, O6-Methylguanine-DNA-methyltransferase, or MGMT, plays an important role in how the body repairs damage to DNA in both men and women. But researchers did not find an association between MGMT and Alzheimer's in men.

"It's a female-specific finding -- perhaps one of the strongest associations of a genetic risk factor for Alzheimer's in women," said senior study coauthor Lindsay Farrer, chief of biomedical genetics at Boston University School of Medicine.

Two-thirds of the 6.5 million Americans currently living with the devastating brain disease are women, according to the Alzheimer's Association. It's a trend that holds true worldwide.

"Women, due to unique genetic risk factors like APOE ε4 and MGMT, and sex-specific risk factors like the sudden reduction in estrogen during the peri-menopause transition, may be in the fast-lane toward the disease, while men are sitting in traffic," said 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.

The APOE ε4 gene is considered the strongest risk factor for the future development of Alzheimer's in people over the age of 65, which is "especially true for women, who are more impacted by APOE ε4 than men," Isaacson said.

However, many women with APOE ε4 don't develop Alzheimer's, while women without the gene may still develop the disease.

"Perhaps MGMT is an important missing piece of the risk prediction puzzle for these women, but further studies are necessary," Isaacson said.

A LUCKY DISCOVERY

The discovery of the new gene's existence was made in two completely separate groups of people. A team of researchers from the University of Chicago were analyzing the genetic makeup of a small group of Hutterian Brethren women who live communally in rural Montana and South Dakota. Hutterites are a closed population who intermarry within their own ranks and keep extensive genealogical records, making them an excellent choice for genetic research.

"The relatively uniform environment and reduced genetic variation in Hutterites increases our power to find associations in smaller sample sizes than required for studies in the general population," said senior study coauthor Carole Ober, chair of human genetics at the University of Chicago, in a statement.

When the new association with MGMT popped up in her analysis, Ober reached out to Boston's Farrer to see if he might help replicate her findings.

Farrer, who was in the midst of a huge genetic analysis of over 10,000 women from the Alzheimer's Disease Genetics Consortium study, was surprised by the call.

"I told her we'd found the exact same gene in our analysis," Farrer said. "Two different studies started independently of one another find by serendipity the same gene, which to me adds a lot of confidence that the finding is robust."

The combined study was published Thursday in Alzheimer's Disease & Dementia: The Journal of the Alzheimer's Association.

A RISK FACTOR FOR WOMEN WITHOUT APOE Ε4

The research team compared the findings to autopsied male brain tissue, and found no association between the MGMT gene and Alzheimer's in men.

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

The association between MGMT and amyloid plaques and tau tangles was "most pronounced in women who don't have APOE ε4," Farrer said.

Considered an essential protein, a primary function of APOE is to "move cholesterol around in your body, and without that you'd be in trouble," Farrer said. However, studies have found that the APOE ε4 variation may result in depositing more fatty acid buildup than the other members of the APOE family, thus leading scientists to believe there is a cholesterol pathway to Alzheimer's.

In fact, a study by Farrer that published in March found having high cholesterol and blood sugar in your 30s may raise your risk for Alzheimer's disease decades later in life.

"There are many pathways to Alzheimer's disease. There's the lipid, or cholesterol pathway, which is now pretty well established in Alzheimer's, and APOE ε4 is a part of that," Farrer said.

"And there's the inflammatory pathway, which is common to all chronic disease. With MGMT, we may be looking at an additional pathway somehow related to DNA repair, or maybe MGMT participates in one of these other pathways and nobody knows yet how," Farrer added.

PERSONALIZED MEDICINE

Women should work with their doctors to try to identify which path they may be on, experts advise.

Interventions could include keeping blood pressure, cholesterol and blood sugar in healthy ranges, while "considering hormone replacement therapy when indicated, and advocating for a brain healthy lifestyle, including regular exercise, a Mediterranean-style diet, adequate sleep and stress-reduction techniques," Isaacson said.

At some point soon, scientists will be able to offer more personalized medicine to women, said Dr. Kellyann Niotis, a neurologist at the Alzheimer's Prevention Clinic at Weill Cornell Medicine and NewYork-Presbyterian, who was not involved with the study.

"We will soon be able to offer women at risk more advanced assessments, like comprehensive genetic testing in a clinic setting, to more adequately assess their risk and develop personalized risk reduction plans for optimal brain protection," Niotis said.