Female Chromosome May Hold The Key to Resilience Against Alzheimer’s

By | August 27th, 2020

New research has uncovered proteins coded by genes of the female sex chromosome that may explain why women are more resilient to the disease.

While women are more likely to develop Alzheimer’s than men, accounting for two-thirds of the 5.8 million Americans living with Alzheimer’s, the two sexes experience different trajectories when they have the disease: Not only do women with Alzheimer’s experience less severe symptoms early on, but they also live longer than men with Alzheimer’s. Now, researchers have found a clue as to the source of this resilience buried in the female sex chromosome.

In a study published this week in Science Translational Medicine, Dena Dubal, an associate professor of neurology at the University of California San Francisco and colleagues discovered that proteins from genes in the X chromosome were linked to improved brain functions, potentially thwarting the harm associated with beta-amyloid, the hallmark protein of the disease. 

“I’m particularly excited because maybe the X chromosome can reveal a new therapeutic path to this horrible disease for which we have no effective treatment,” Dubal told Being Patient. 

Her research team first confirmed that men with Alzheimer’s die earlier than women with the disease. After analyzing data of human populations worldwide, they found that men with Alzheimer’s are over 60 percent more likely to die earlier than their female counterparts.

“This is a really interesting [study] because it involves both human and mouse data, which a lot of studies don’t,” said Jessica Caldwell, director of the Women’s Alzheimer’s Movement Prevention Center at Cleveland Clinic, who was not involved in the study. “And it looks at the sex difference in Alzheimer’s disease from a perspective that I don’t hear about as much, which is: In what way are men at more of a disadvantage?”

While men only have one X chromosome, women have two X’s, increasing their chances of carrying two copies of an especially potent variant of the KDM6A gene that codes for the protective protein. By analyzing databases of gene expression, the researchers found that about 13 percent of women and seven percent of men worldwide carry this variant, known as rs12845057. 

This genetic variant may slow down Alzheimer’s progression  

When Dubal’s team examined long-term studies of older adults, many of whom had mild cognitive impairment, which can be a precursor to Alzheimer’s, they found that women with one copy of rs12845057 appeared to progress more slowly toward Alzheimer’s than women without the variant. Women who carried two copies of the variant seemed to advance even more slowly towards Alzheimer’s.

Though it’s unclear whether the same holds true for men who carry the variant as there were too few of them in the study to determine. 

The protective proteins might boost cognitive performance and longevity

By analyzing gene expression studies, the researchers found that women had a larger quantity of the protective proteins in their brain than men.  

Those with Alzheimer’s had higher levels of the protective proteins in the brain regions like the hippocampus that is damaged early in the course of the disease. 

Perhaps the neurons in these brain regions produced more of the proteins to fight against the diseases, the researchers suggested.  

To examine their theory, they turned to experiments with mice. When they exposed neurons from male and female mouse brains to increasing doses of beta-amyloid, the male neurons died faster. 

They also found that male mice with Alzheimer’s who had a second X chromosome performed better on cognitive tests and lived longer compared to male mice with the disease that didn’t carry the extra X. 

To confirm that the second X chromosome protected the mice from Alzheimer’s, the scientists deleted the second X chromosome from female mice with Alzheimer’s. Subsequently, they found the mice became more cognitively impaired and died faster.  

The team then increased the expression of KDM6A in a region of the hippocampus known as the dentate gyrus, which is involved in spatial learning and memory, in male Alzheimer’s mice. A month later, the male mice had just as many protective proteins in the dentate gyrus as female mice. These males performed much better in spatial memory tests than those without the increased expression of KDM6A. 

Despite this protection, women are still at a higher risk of developing Alzheimer’s

While women may be more resilient when they have Alzheimer’s, researchers also know that they are at a higher risk of developing the disease. Dubal believes that is largely due to the fact that women live until the ages when the risk and incidence of Alzheimer’s is the highest. According to the study, after the age of 85, women are at an increased risk of developing Alzheimer’s than men. 

Jessica Caldwell noted that other contributing factors may also include that Alzheimer’s has been linked to the drop in estrogen levels that accompanies menopause. Studies have also found that women with the ApoE4 gene are more likely to develop the disease than men with a copy of ApoE4. And, women with comorbidities like cardiovascular risks, may experience more long-term cognitive decline. 

What’s next?

While a potential Alzheimer’s treatment may lie in boosting people’s levels of the protective proteins, Dubal said scientists still have long ways to go until they can develop therapies targeting the KDM6A gene.

In future research, the team said they hope to better understand the functions of KDM6A in brain cells and delve deeper into the interaction between the gene, beta-amyloid and tau, another hallmark abnormal protein in Alzheimer’s. They also hope to learn whether KDM6A is linked to aging and other forms of dementia such as Parkinson’s and frontotemporal dementia. 

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