Gene Discovery May Explain Why More Women Get Alzheimer's Disease
Health and Well Being
August 25, 2022
Gene Discovery May Explain Why More Women Get Alzheimer's Disease
Mature mother and daughter at the kitchen table

If Alzheimer’s disease runs in your family, or you know someone who has had Alzheimer’s, you know firsthand how frightening it can be to wonder if one day you too will develop the disease. You may even feel a bit helpless because, as of today, there is no cure, treatment to substantially slow the progression of the disease, or surefire prevention. To add to it, women are disproportionately affected over men, with women’s risk of developing the disease almost twice as high as their male counterparts.

However, scientists have recently identified a gene that may provide a potential new clue as to why more women than men are diagnosed with the disease. The gene is referred to as O6-Methylguanine-DNA-methyltransferase, or MGMT.

To gain some insight into this discovery and what it could mean as we continue to fight for a cure for Alzheimer’s, we spoke with Claudia Perez, M.D., a neurologist and physician on the medical staff at Texas Health Specialty Hospital, and at Neurocritical Care Associates, a Texas Health Physicians Group practice.

Why Women May Be at a Higher Risk

There are a few explanations for why women seem to be at a higher risk than men. For starters, women tend to live longer than men, and your risk for developing Alzheimer’s substantially increases as you age. For instance, only 4 out of 1,000 people ages 65 to 74 develop Alzheimer’s each year, but that number jumps up to 32 once you hit 75 years old. After 85, the number increases to 76 out of 1,000 people.

Another risk factor has to do with how Alzheimer’s takes hold. Alzheimer's is characterized by a build-up of amyloid-β and tau proteins in the brain. Research has shown that estrogen may help to protect the brain from Alzheimer's by blocking some of the harmful effects of the amyloid-β protein. But women experience a sudden reduction in estrogen during the transition to menopause, losing those possibly protective benefits.

However, genetics play a pivotal role in the development of Alzheimer’s.

“Prior to this study, we already knew that having the APOE ε4 gene was, and still is, the strongest genetic risk factor for sporadic Alzheimer’s disease in both men and women,” Perez explains. “However, the mechanisms for why the effect is greater in women are not yet fully understood, especially considering the fact that many women with the gene don’t go on to develop Alzheimer’s, while women without the gene may still develop the disease.”

The discovery of the MGMT gene may be an important missing piece in the risk prediction puzzle for these women.

The discovery comes to us from two separate studies which were combined and published in Alzheimer's Disease & Dementia: The Journal of the Alzheimer's Association.

Researchers compared their findings to autopsied male brain tissue and found no association between the MGMT gene and Alzheimer's in men. However, when they examined MGMT via epigenetics, which is what happens when a gene is switched on or off by behaviors and environmental factors, researchers found its expression in women was significantly associated with the development of amyloid-β and tau proteins.

The association between MGMT and these proteins was higher in women who don't have the APOE ε4 gene versus those who do, giving us a potential explanation for why women who do not have the APOE ε4 gene can still go on to develop Alzheimer’s.

The primary function of APOE is to move cholesterol around in your body, but a recent study has found that the APOE ε4 variation may result in depositing more fatty acid buildup than the other members of the APOE family, thus leading scientists to believe cholesterol plays a role in the development of Alzheimer’s.

In fact, one of the researchers in the study had previously published a separate study earlier this year stating that having high cholesterol and blood sugar in your 30s may raise your risk for Alzheimer's disease decades later in life.

Perez notes that there are many pathways to Alzheimer's disease. There's the cholesterol pathway, which we just discussed, and there’s also an inflammatory pathway, which is common to all chronic disease.

“MGMT plays an important role in how the body repairs damage to DNA,” Claudia says. “With MGMT, we may be looking at an additional pathway somehow related to DNA repair. There’s also the possibility that MGMT participates in one of these other pathways and we just don’t know it yet.”

What to Take Away from This Study

While this discovery is an exciting new development in understanding the unique causes of Alzheimer’s disease, Perez says it’s still hard to predict who will develop it based on genetics alone, as there are sporadic cases of Alzheimer’s disease in the absence of a family history and known genetic markers.

“The causes probably include a combination of genetic, environmental, and lifestyle factors,” she adds. “The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer’s may differ from person to person. That being said, the best thing you can do for yourself is to understand your personal risk factors. This can empower you to make lifestyle changes that may impact your risk for Alzheimer’s disease in the future.”

There are many things you can do to reduce your risk of Alzheimer’s, whether you’re male or female:

  • Engage in brain and heart-healthy aerobic exercise such as brisk walking, jogging, biking, swimming, or aerobic classes for at least 30 minutes per day, five days per week.
  • Eat a Mediterranean menu of foods including fish, olive oil, avocados, fruits, vegetables, nuts, beans, whole grains, and poultry.
  • Keep your blood pressure, blood sugar and cholesterol in healthy ranges.
  • Consult with your physician if hormone replacement therapy is right for you during and after menopause.
  • Sleep well to help clean those Alzheimer’s plaques in your brain.
  • Lower your stress levels.
  • Participate in social activities and cognitively stimulating activities.

“The hope for the future is that science will be able to offer more personalized medicine to women based on comprehensive genetic testing to more adequately assess their risk and develop personalized risk reduction plans for optimal brain protection,” Perez says. “Until then there is still a lot that you can do to reduce the risk through promoting a healthy lifestyle.”

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