Gene discovery may explain why more women get Alzheimer’s 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 found no link between MGMT and Alzheimer’s disease in men.

“It’s a female-specific finding — perhaps one of the strongest associations of a genetic risk factor for Alzheimer’s disease in women,” said study co-author Lindsay Farrer, chief of biomedical genetics at Boston University School of Medicine.

“Women, because of unique genetic risk factors such as APOE ε4 and MGMT, and gender-specific risk factors such as the sudden reduction in estrogen during the transition to menopause, may be in the fast lane to disease, while men are 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 disease in people over 65, which is “particularly true for women, who are more affected by APOE ε4 than men,” Isaacson said.

Many women with APOE ε4 don’t get Alzheimer’s, while women without the gene can still get the disease.

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

A happy discovery

The discovery of the existence of the new gene was made in two completely different groups of people. A team of researchers from the University of Chicago analyzed 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 that 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 enhances our ability to find associations in smaller sample sizes than is required for studies in the general population,” said study co-senior Carole Ober, chair of human genetics at the University. of Chicago, in a statement.

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

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

“I told her we found the exact same gene in our analysis,” Farrer said. “Two different studies that were started independently of each other found the same gene through serendipity, which gives me 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 with autopsy of male brain tissue and found no link between the MGMT gene and Alzheimer’s disease in men.

When they examined MGMT through epigenetics, what happens when a gene is turned on or off by behavior and environmental factors, researchers found that its expression in women was significantly associated with the development of beta-amyloid and tau, two proteins characteristic of Alzheimer’s disease. 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 “move cholesterol in your body, and without it you’d be in trouble,” Farrer said. However, studies have shown that the APOE ε4 variation can result in more fatty acid buildup than the other members of the APOE family, leading scientists to believe there is a cholesterol pathway to Alzheimer’s disease.
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In fact, a study by Farrer published in March found that high cholesterol and high blood sugar in your 30s can increase your risk of Alzheimer’s disease decades later in life.

“There are many pathways to Alzheimer’s disease. There is the lipid or cholesterol pathway, which is now quite well established in Alzheimer’s disease, and APOE ε4 is part of that,” Farrer said.

“And there’s the inflammatory pathway, which all chronic diseases have in common. With MGMT, we may be looking at an additional pathway that is somehow related to DNA repair, or maybe MGMT is participating in one of these other pathways and nobody remember how,” Farrer added.

Personalized Medicine

Women should work with their doctors to try to determine which path they are on, experts advise.

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

Interventions may include keeping blood pressure, cholesterol, and blood sugar within healthy limits, while considering “hormone replacement therapy as indicated,” and advocating healthy lifestyles for the brain, including regular exercise, a Mediterranean diet, adequate sleep, and stress reduction techniques,” said Isaacson.

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 in the study.

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

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