Gene discovery could explain why more women are getting Alzheimer’s disease

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

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

“Women, due to unique genetic risk factors like APOE ε4 and MGMT, and gender-specific risk factors like sudden reduction in estrogen during the peri-menopausal transition, may be on the fast track to disease, while that men sit 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 to be the most important risk factor for the future development of Alzheimer’s disease in people over the age of 65, which is “especially true for women, who are more affected by Alzheimer’s disease. APOE ε4 than men,” Isaacson said.

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

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

A happy discovery

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

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

When the new association with MGMT appeared in his analysis, Ober contacted Farrer of Boston to see if he could help him replicate his findings.

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

“I told him we found the exact same gene in our analysis,” Farrer said. “Two different studies launched independently of each other come across the same gene, which for 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 results to autopsied male brain tissue and found no association between the MGMT gene and Alzheimer’s disease in men.

When they looked at MGMT via epigenetics, i.e. what happens when a gene is turned on or off by behaviors and environmental factors, the researchers found that its expression in women was significantly associated with the development of beta-amyloid and the tau protein, two proteins characteristic of Alzheimer’s disease. sickness.

The association between MGMT and amyloid plaques and tau tangles was “more pronounced in women who lack APOE ε4,” Farrer said.

Considered an essential protein, one of APOE’s main functions is to “move cholesterol around your body, and without it, you’d be in trouble,” Farrer said. However, studies have shown that the APOE ε4 variation may result in the deposition of greater fatty acid accumulation than other members of the APOE family, leading scientists to believe that 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 blood sugar levels in your 30s can 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 quite well established in Alzheimer’s disease, and APOE ε4 is one of them,” Farrer said.

“And there’s the inflammatory pathway, which is common to all chronic diseases. With MGMT, maybe we’re looking at an additional pathway that somehow relates to DNA repair, or maybe be that MGMT participates in one of these other pathways and no one yet knows how,” Farrer added.

Personalized medicine

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

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

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

At some point, scientists will soon be able to provide more personalized medicine for women, said Dr. Kellyann Niotis, a neurologist at the Alzheimer’s Disease Prevention Clinic at Weill Cornell Medicine and NewYork-Presbyterian, who has no participated in the study.

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

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