February 9, 2023

A gene could explain why more women have Alzheimer’s

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(CNN) — Scientists have identified a gene that appears to increase the risk of Alzheimer’s in women, providing a possible 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 DNA damage in both men and women. But the researchers found no link between MGMT and Alzheimer’s in men.

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

Two-thirds of the 6.5 million Americans currently suffering from this devastating brain disease are women, according to the Alzheimer’s Association. It is a trend that continues throughout the world.

“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 perimenopausal transition, may be in the fast lane to disease, while that men are sitting in traffic,” said Dr. Richard Isaacson, director of the Alzheimer’s Prevention Clinic at Florida Atlantic University 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 years of age, which is “especially true for women, who are more affected by APOE ε4 than men Isaacson said.

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

“Perhaps [el gen] MGMT may be an important missing piece of the risk prediction puzzle for these women, but more study is needed,” Isaacson said.

a lucky find

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 was analyzing the genetic makeup of a small group of Hutterite women who live communally in rural Montana and South Dakota. The Hutterites are a closed population that intermingle within their own ranks and maintain extensive genealogical records, making them an excellent choice for genetic research.

“The relatively uniform environment and low genetic variation of the Hutterites increase our ability to find associations in smaller samples than is required for studies in the general population,” said study co-senior author Carole Ober, professor of human genetics at the University of Chicago, in a statement.

When the new association with the MGMT gene showed up in his analysis, Ober contacted Farrer of 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 from the Alzheimer’s Disease Genetic Consortiumwas surprised by the call.

“I told him that we had found the exact same gene in our analysis,” Farrer said. “Two different independently initiated studies found the same gene by chance, which adds a lot of confidence to me that the finding is robust.”

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

A risk factor for women without the APOE ε4 gene

The research team compared the findings with male brain tissue from autopsies, and found no association between the MGMT gene and Alzheimer’s in men.

When they examined MGMT through epigenetics, 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 amyloid beta and tau proteins, features of Alzheimer’s disease.

The association between MGMT and amyloid plaques and tau tangles was “more pronounced in women who did not have APOE ε4,” Farrer said.

Considered an essential protein, one of APOE’s main jobs is “to move cholesterol around the body, and without that we’d be in trouble,” Farrer said. However, studies have revealed that the APOE ε4 variation can result in more fatty acid deposition than other members of the APOE family, leading scientists to believe that there is a cholesterol pathway to Alzheimer’s.

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

The Long-Term Effects of High Cholesterol and Glucose 1:08

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

“And there’s the inflammatory pathway, which is common to all chronic diseases. With MGMT, we may be looking at an additional pathway related to DNA repair in some way, or MGMT may be involved in one of these other pathways and no one still know how,” added Farrer.

Personalized medicine

Experts advise that women work with their doctors to try to identify the way forward.

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

At some point, scientists will soon be able to offer more personalized medicine to women, said Dr. Kellyann Niotis, a neurologist with 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 screenings, such as comprehensive genetic testing in a clinical setting, to better assess their risk and develop personalized risk reduction plans for optimal brain protection,” said Niotis.



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