Genetic study may explain why women develop Alzheimer’s more than men

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A research team has 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 gene damage in men and women. But so far, researchers haven’t found an association between MGMT and Alzheimer’s in men.

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“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-senior author Lindsay Farrer, head of biomedical genetics at the University of California School of Medicine. Boston.

Two-thirds of the 6.5 million Americans currently living with the devastating brain disease are women, according to the Alzheimer’s Association. It is a trend that is valid all over the world.

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“Women, due to unique genetic risk factors such as APOE ε4 and MGMT, and sex-specific risk factors such as the sudden drop in estrogen during the perimenopause transition, may be on the fast lane towards disease, while men are sitting in traffic,” said Richard Isaacson, director of the Alzheimer’s Prevention Clinic at the Atlantic University of Florida’s Schmidt School 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 “especially true for women, who are more affected by APOE ε4 than men.” , said Isaacson.

However, 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 piece of the risk prediction puzzle for these women, but more studies are needed,” said Isaacson.

a lucky discovery

The discovery of the existence of the new gene was made in two completely separate groups of people. A team of researchers at the University of Chicago was analyzing the genetic makeup of a small group of female Hutterian Brothers living in a community in rural Montana and South Dakota.

The Hutterites are a closed population that intermarry among their own ranks and maintain extensive genealogical records, making them an excellent choice for genetic research.

“The relatively uniform environment along with the reduced genetic variation in the Hutterites enhances our power to find associations in smaller samples than needed for general population studies,” said study co-author and University of Chicago Chair of Human Genetics Carole Ober. , in a statement.

When the new association with MGMT appeared in his analysis, Ober reached out to Farrer, from Boston, to see if he could help replicate his findings.

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

“I told her that we found the exact same gene in our analysis,” Farrer said. “Two different studies started independently of each other happened to find the same gene, which to me adds a lot of confidence that the finding is robust.”

The combined study was published in the scientific journal 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 examined the epigenetic pathway of MGMT, which is 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 tau, two proteins that are characteristic of Alzheimer’s disease.

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

Considered an essential protein, APOE’s primary function is “to move cholesterol through the body, and without that, you’d be in trouble,” Farrer said.

However, studies have found that the APOE ε4 variation may result in the deposit of more fatty acid accumulation than the other members of the APOE family, leading scientists to believe that there is a link between cholesterol and Alzheimer’s disease.

Preventive measures may delay the development of Alzheimer's

In fact, a study by Farrer, published in March, found that having high cholesterol and blood sugar at 30 years can increase the risk of Alzheimer’s disease decades later in life.

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

“And there is the inflammatory pathway, which is common to all chronic diseases. 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 no one knows yet how,” she added.

personalized medication

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

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

At some point, scientists will be able to offer more personalized drugs to women, said 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 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,” Niotis said.

Source: CNN Brasil

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