Women with Alzheimer’s live longer than men with the disease.
In a new study, researchers found evidence from both humans and mice that this is because they have genetic protection from the ravages of the disease.
By virtue of having a second X chromosome, women get two “doses” of a protective protein from a gene that only exists on this female sex chromosome.
Some people, both male and female, have an especially potent variant of this gene, which is called KDM6A, which gives them even more protection.
But, because of the way sex chromosomes work—women have two X’s, but men only have one—women have two copies of this gene churning out the protective protein.
The new study offers a first look at how sex chromosomes affect vulnerability to Alzheimer’s.
And it helps explain why women survive longer and with less severe symptoms than men during the early stages of the disease, even when they have comparable levels of toxic Alzheimer’s proteins in their brains.
The researchers say that this finding challenges a long-standing dogma that women are more vulnerable to Alzheimer’s.
More women than men have Alzheimer’s because they survive to older ages when risk is highest. But they also survive with the disease for longer.
The research was conducted by scientists at UC San Francisco.
While much of a female’s second X chromosome is “silenced” by an outer layer of non-coding RNA, a small number of genes escape this process, in both mice and humans, giving females twice the dose of the proteins coded for by those genes.
The researchers zeroed in on one of these active genes, KDM6A, which is already known to be involved in learning and cognition: when this gene malfunctions, it causes Kabuki syndrome, characterized by developmental delay and mild to severe intellectual disability.
Combing through public databases of gene expression studies, the scientists discovered an especially active variant of KDM6A that is carried by about 13% of women and 7% of men around the world.
Because women have two X chromosomes, they have a greater chance of carrying at least one copy of this variant, and some women carry two copies.
When the scientists looked at several long-term studies of older people, many of whom already had mild cognitive impairment, they could see that women with one copy—or even better, two copies—of the variant appeared to progress more slowly toward Alzheimer’s.
It’s not yet clear if the same holds true for men who carry the variant on their X chromosome, since there may have been too few of them in the study to see any effects.
The gene expression research showed that women in general had more KDM6A protein in their brains than men.
They also showed that people with Alzheimer’s had more of the protein in brain regions that get damaged early in the disease.
The researchers theorized that neurons in these regions may produce more of the protein to protect against the disease, although the data they analyzed could only identify associations, and not prove causes.
To get closer to this causal question, the scientists performed experiments in mice.
First, they found female mice had much higher levels of KDM6A protein in a brain region called the hippocampus, which is critical to learning and memory and gets damaged early in Alzheimer’s.
Then they bred mice that model human Alzheimer’s by producing toxic amyloid-beta in their brains, so their male offspring produced amyloid and also carried two X chromosomes like females.
With a second X chromosome, the male mice did better on cognitive tests, and they also lived longer, despite the toxic proteins in their brains.
In further tests, when the scientists exposed neurons from male and female mouse brains to increasing doses of amyloid-beta, the male neurons died faster.
But this difference was eliminated when the scientists used a gene-editing technique to reduce Kdm6a protein levels in the females’ brains and increased it in the neurons from male mouse brains.
These findings show a new role for sex chromosomes. The team says this protective mechanism on the X chromosome opens the possibility that people could increase resilience to Alzheimer’s and other neurodegenerative disorders by boosting Kdm6a or other X factors in both men and women.
One author of the study is Dena Dubal, MD, Ph.D., an associate professor of neurology at UCSF.
The study is published in Science Translational Medicine.
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