Scientists spot gene that may explain why more women get Alzheimer's

• Alzheimer’s disease (AD) affects nearly twice as many women as men.
• About 60% of people with AD don’t express apolipoprotein E (APOE ε4), its most established genetic risk factor.
• New research has shown the MGMT gene may be associated with a higher risk of AD in two different populations, particularly in women without APOE ε4.
• The study found that the expression of MGMT contributes to the development of toxic proteins associated with Alzheimer’s, especially in women.

AD is the most common form of dementia, a gradual condition that causes the brain to shrink and the cells to die. The condition affects a person’s ability to remember, think, and carry out simple tasks.

According to the Centers for Disease Control and Prevention (CDC), over 5.8 million people in the U.S. are living with AD and dementia, which is predicted to rise to nearly 14 million by 2060.

AD is caused by the toxic buildup of amyloid proteins around the brain cells and tau proteins inside the brain cells.

Genetic studies have linked AD risk to the gene APOE ε4, however, 60% of people with AD do not carry the gene, suggesting that other genes may be involved in the condition.

A recent study suggests that a new gene could be linked to a higher risk of developing Alzheimer’s, particularly in women.

The study is published in Alzheimer’s Disease & Dementia: The Journal of the Alzheimer’s Association.

Gender differences in AD

According to the Alzheimers Association, women are nearly twice as likely to be affected by AD than men. This is thought to be due to them living longer.

“[..] women over 60 are twice as likely to develop Alzheimer’s disease, […] than they are to develop breast cancer during the rest of their lifetime,” explained Dr. Rosa Sancho, the head of research at Alzheimer’s Research, who was no involved in the study.

Researchers trying to understand these differences have shown changes in the tau gene (MAPT) region in women with breast cancer, people with AD without APOE ɛ4, and women with ovarian cancer.

In a new study using genome-wide sequencing (GWAS), researchers from the Boston University School of Medicine, University of Chicago, and the University of Pennsylvania, among others, found a gene called MGMT which may increase the risk of AD in women.

The gene linked to Alzheimer’s

To understand if other genes involved in tau-related diseases are related to AD risk in women, the researchers performed GWAS on two different populations:

• 31 members of the Hutterites, a group of people with common ancestry, recognized for their relatively small gene pool, 22 of whom were women.
• 10,340 women without APOE ɛ4, who were part of the Alzheimers Disease Genetics Consortium (ADGC). These included 3,399 AD cases and 6,905 controls.

Researchers found that in both populations, the MGMT gene was associated with AD risk in women lacking APOE ɛ4.

“[..] The fact that studies with such different designs identified (different) genetic variants that were linked to the same gene was unexpected,” said Dr. Carole Ober, chair of human genetics at the University of Chicagoand joint study lead.

“The different lines of evidence supporting a role for MGMT in Alzheimer’s disease risk increased our confidence,” she said.

The work suggests that the expression of MGMT contributes to the development of toxic amyloid and tau proteins associated with the development of AD.

The underlying mechanism

To understand the mechanisms behind the link, the researchers analyzed the brain tissue of 177 participants of the Framingham Heart Study, 58 with confirmed AD.

Speaking to Medical News Today about the mechanisms behind the findings, Dr. Ober explained:

“Our data suggest that the associated genetic variants affect levels of DNA methylation and/or other epigenetic marks, like open chromatin, and these epigenetic changes impact the expression of MGMT at key developmental stages […] is our current working hypothesis.”

“This research also highlights just how complex Alzheimer’s is, with the MGMT gene involved in a number of cellular processes that could contribute to the development of disease.”
— Dr. Rosa Sancho

The take-home message

According to Ober, the study’s take-home message is “[…] an Alzheimer’s disease gene may impart its risk effects only in females and that epigenetic remodeling in neurons may be an important mediator of this risk.”

The next steps, he says, “are to first directly show that the genetic variants are involved in this epigenetic remodeling and then study the downstream effects of the remodeling in cell models of neuron development.”

“It’s going to take a concerted and global effort to develop life changing treatments, but genetic discoveries like this are a step in the right direction,” noted Dr. Sancho when asked about the significance of the study.

“The more we understand about risk genes and how they affect the development of Alzheimer’s, the closer we can get to new treatment approaches for the disease.”
— Dr. Rosa Sancho

Dr. Jennifer Bramen, senior research scientist at Providence Saint John’s Health Center, who was also not involved in the study, echoed these thoughts.

“Future research may find that the MGMT variants identified by this work […] may potentially lead to the identification of new drug targets or biomarkers—all important in treating and researching Alzheimer’s disease,” she said.

Dr. Bramen went on to say that “Lifestyle factors like walking, regular aerobic exercise, eating a healthy diet filled with fresh produce […] will do a lot to prolong cognition. As at-risk women grow older and lose the brain protection provided by estrogen, it is even more important that they take care of their health.”

“The brain is not separate from the body. Physical health is brain health, and therefore highly impacts cognitive abilities,” she added.

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