This Gene May Be Why Women with Alzheimer’s Disease Live Longer Than Men

• Researchers say a gene called KDM6A may explain why women with Alzheimer’s disease tend to live longer than men with the same condition.
• They found evidence that KDM6A protein helps slow cognitive decline and improve survival in those with Alzheimer’s disease.
• Compared with men, women are more likely to develop Alzheimer’s disease. Women account for nearly two-thirds of Americans affected by it.
• Alzheimer’s disease tends to progress more quickly in men. They tend to experience more rapid cognitive decline and die sooner.

Women with Alzheimer’s disease tend to live longer than men with the disease — and a new study suggests that a gene on the X chromosome may help explain why.

Each person typically has one pair of sex chromosomes in each cell of their body. People assigned female at birth typically have two X chromosomes, while people assigned male at birth typically have one X chromosome and one Y chromosome.

Researchers say a gene called KDM6A may explain why women with Alzheimer’s disease tend to live longer than men with the same condition.

The gene is only found on X chromosomes. It tells the body how to produce the KDM6A protein, which is known to play a role in cognition.

In a study published last week in the journal Science Translational Medicine, researchers investigated the effects of the KDM6A gene in humans and mice.

They found evidence that KDM6A protein helps slow cognitive decline and improve survival in those with Alzheimer’s disease.

“The gene KDM6A was found to have protective effects on the brain. Thus, the more doses of the gene — i.e., XX vs. XY — the better resilience,” Michelle M. Mielke, PhD, director of the Specialized Center of Research Excellence on Sex Differences at Mayo Clinic College of Medicine in Rochester, Minnesota, told Healthline. She wasn’t involved in the study.

“A next step in this research will be to identify other genes on the X or Y chromosomes that are beneficial or detrimental to the brain,” Mielke added. This will help experts develop a “better understanding of some of the pathways that can protect the brain and therefore be potential drug targets.”

Alzheimer’s disease affects women differently

Compared with men, women are more likely to develop Alzheimer’s disease. Women account for nearly two-thirds of Americans affected by it.

On the other hand, Alzheimer’s disease tends to progress more quickly in men. They tend to experience more rapid cognitive decline and die sooner.

Past studies have found that sex-related differences in hormones, immune function, and energy metabolism may help account for these gaps.

The new study on KDM6A adds another piece to the puzzle, highlighting the role that non-hormone-related genes on sex chromosomes may play.

“The Alzheimer’s Association held a think tank in 2015 to explore the biology that may contribute to sex differences in Alzheimer’s disease,” Heather M. Snyder, PhD, the Alzheimer’s Association’s vice president of medical and scientific engagement, told Healthline.

“One of the outstanding questions from that think tank was that we did not yet have the tools to fully evaluate the impact of the X or Y chromosome.”

She added that the new study is “helping to start to address some important scientific questions” by using “emerging technologies to look at the complexity of the X chromosome.”

Looking to mice for insights

To assess the potential role of X chromosomes in Alzheimer’s disease, the authors of the new study conducted a series of experiments in a mouse model of the disease.

They found that male mice with Alzheimer’s disease demonstrated greater cognitive impairments and died more quickly than female mice.

When they genetically engineered male mice with Alzheimer’s disease to have two X chromosomes, those mice performed better on cognitive tests and lived longer than male mice with one X chromosome.

Conversely, female mice that were engineered to have only one X chromosome showed more cognitive impairment and died more quickly than those with two X chromosomes.

“The authors show that the addition of an X leads to brain resilience,” Mielke explained. “Notably, it is not that the Y gene is necessarily detrimental, just that having two X chromosomes, indicative of females, offers more brain protection.”

Exploring the role of KDM6A

The authors of the new study suspected the KDM6A gene may help account for the differences observed in mice with one versus two X chromosomes.

When mice have two X chromosomes, most of the genes on the second X chromosome are inactivated. But KDM6A is one of a small group of genes that remains active on both chromosomes.

After reviewing a public dataset of gene expression studies, the researchers found that about 14 percent of people carry a particularly active variant of the KDM6A gene.

This variant of the gene wasn’t associated with lower risk of developing Alzheimer’s disease, but it was linked to slower cognitive decline in people who have the disease.

When the researchers engineered male mice with Alzheimer’s disease to produce more KDM6A protein than usual, they found the mice performed much better than average on cognitive tests.

Developing new strategies to treat Alzheimer’s

The findings of this study may help experts understand why symptoms of Alzheimer’s disease develop more quickly in some people than in others.

“As we understand more about Alzheimer’s pathology, we know that some patients with significant pathology may not develop any clinical symptoms — and protection from genes such as KDM6A may offer clues as to why,” said Dr. Gayatri Devi, a neurologist at Lenox Hill Hospital in New York City and author of “The Spectrum of Hope: An Optimistic and New Approach to Alzheimer’s Disease and Other Dementias.”

In turn, identifying protective genes and other biological factors that shape the progression of the disease may help researchers develop more effective prevention, diagnosis, and treatment strategies.

“Understanding the biological differences of Alzheimer’s between the sexes would potentially be a huge benefit to the field in researching and developing more specific diagnostic tools, therapies, and preventions,” said Snyder.

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