Discovery of genes could explain why more women develop Alzheimer’s disease

The gene O6-methylguanine DNA methyltransferase, or MGMT, plays an important role in how the body repairs DNA damage in both males and females. However, researchers found no link 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 females,” said Lindsay Farrer, co-author of the lead study, chief of biomedical genetics at Boston University School of Medicine.

“Women may be in the fast lane toward the disease while men are sedentary because of unique genetic risk factors, such as APOE ε4 and MGMT, and gender-specific risk factors, such as the sudden drop in estrogen levels during the transition to perimenopause,” said Dr. Richard Isaacson, director of 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 thought to be the strongest risk factor for future development of Alzheimer’s in people over the age of 65, which “is particularly true for women, who are more affected by APOE ε4 than men,” Isaacson said.

Many women with APOE ε4 do not develop Alzheimer’s, while women without the gene can still develop the disease.

“Perhaps MGMT is an important missing piece in the risk prediction puzzle for these women, but further studies are needed,” Isaacson said.

A happy 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 analyzed the genetic makeup of a small group of Hutterian Brethren females living together in rural Montana and South Dakota. Hutterites are a cohesive population who intermarry within their own ranks and maintain extensive genealogical records, making them an excellent choice for genetic research.

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“The relatively uniform environment and reduced genetic variation in Hutterites increases our ability to find associations in smaller sample sizes than are required for studies in the general population,” said lead study co-author Carole Ober, Chair of Human Genetics at the University of Chicago, in a statement.

When the new association with MGMT emerged in her analysis, Ober reached out to Boston-based Farrer to see if he could help replicate her findings.

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

“I told her that we found the exact same gene in our analysis,” Farrer said. “Two different studies started independently found the same gene by chance, which gives me great 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 results to autopsied male brain tissue and found no link between the MGMT gene and Alzheimer’s in men.

When they studied MGMT via epigenetics, what happens when a gene is turned on or off by behavioral and environmental factors, the researchers found that 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 do not have APOE ε4,” Farrer said.

Considered an essential protein, a primary function of APOE is to “transport cholesterol around your body, and without that you’d be in trouble,” Farrer said. However, studies have found that the APOE ε4 variation can cause more fatty acids to accumulate than the other members of the APOE family, leading scientists to believe there may be a cholesterol pathway to Alzheimer’s.

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In fact, a study by Farrer published in March found that high cholesterol and blood sugar in your 30s may increase your risk of 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 fairly well established in Alzheimer’s, and APOE ε4 is part of that,” said Farrer.

“And there’s the inflammatory pathway that’s common to all chronic diseases. With MGMT, we might be looking at an additional pathway that’s somehow related to DNA repair, or maybe MGMT is involved in one of those other pathways and nobody knows how yet,” Farrer added.

Personalized medicine

Women should work with their doctors to figure out what path they’re on, experts advise.

Women need to keep their cholesterol, blood sugar and blood pressure under control to reduce their risk of dementia, experts say.

Interventions could include maintaining blood pressure, cholesterol, and blood sugar in healthy ranges while “considering hormone replacement therapy if needed and advocating a brain-healthy lifestyle including regular exercise, a Mediterranean diet, adequate sleep, and stress reduction techniques,” Isakson said .

Sometime soon, scientists will be able to offer women more personalized medicine, said Dr. Kellyann Niotis, a neurologist at the Alzheimer’s Prevention Clinic at Weill Cornell Medicine and New York-Presbyterian, who was not involved in the study.

“We will soon be able to offer more advanced assessments to at-risk women, such as comprehensive genetic testing in a clinical setting, to more appropriately assess their risk and develop personalized risk reduction plans for optimal brain protection,” Niotis said.