A study from the University of California San Francisco (UCSF) has revealed that women with Alzheimer’s do better than men with the disease due to a genetic advantage conferred by their extra X chromosome. UCSF scientists found that having an additional copy of the sex chromosome gives women two “doses” of a gene found only on that chromosome.
The new research provides insight into how sex chromosomes affect susceptibility to Alzheimer’s, and how they can impact the course and severity of the disease. It helps explain why women with the disease survive longer with less severe symptoms than men during the early stages of Alzheimer’s, despite having the same levels of toxic amyloid beta and tau proteins in their brains.
The study was published in the journal Science Translational Medicine.
The gene, called KDM6A, is a histone demethylase that is believed to function as a tumor suppressor.
The research also found that not only is having two copies of the gene favorable, but having a potent variant of the gene – which both females and males can have – is also beneficial.
It has been thought that women are more vulnerable to Alzheimer’s disease as approximately two-thirds of all Alzheimer’s diagnoses are in women. However, as researchers are now beginning to understand, this is because women live longer than men — giving them more time to develop the disease — and once they do have it, they live better with it than men with the disease.
Women may have more resilience against Alzheimer’s compared to men because the extra copy of the gene on the X chromosome provides protection against some of the devastating effects of the disease.
“This finding challenges a long-standing dogma that women are more vulnerable to Alzheimer’s,” said Dena Dubal, MD, PhD, associate professor of neurology at UCSF and senior author on the study. “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,” explained Dubal, who is also the David Coulter Endowed Chair in Aging and Neurodegenerative Disease, and a member of the UCSF Weill Institute for Neurosciences.
Dubal and her research team looked at sex chromosomes in mice and humans. In a mouse model of Alzheimer’s disease, they found that male mice died faster than female mice. However, addition of a second X chromosome to male mice conferred resilience against the disease, allowing the mice to live longer and perform better on cognitive tests. To further confirm these results, the scientists deleted the second X in female Alzheimer’s mice, which led them to be more cognitively impaired like males and die faster.
The Active Gene
A female’s second X chromosome is typically silenced (so that females don’t get an overdose of X chromosome genes) through X-linked inactivation, a process where the chromosome is coated with an outer layer of non-coding RNA. However, in both mice and humans, a small number of genes escape this process, which gives females twice the dose of protein products encoded by the genes.
One of these doubly active genes is KDM6A. The researchers directed their focus to KDM6A because of its known involvement in learning and cognition. Abnormal functioning of the gene causes Kabuki syndrome, which is characterized by developmental delay and mild to severe intellectual disability.
In the Alzheimer’s mouse model, the scientists found that female mice had significantly higher levels of KDM6A protein in the hippocampus, which is critical to learning and memory and gets damaged early in Alzheimer’s.
Moreover, when the scientists subjected neurons from male and female mouse brains to increasing doses of amyloid beta, the male neurons died faster. This difference could be mitigated when the scientists used a gene editing technique to either reduce KDM6A protein levels in the female-derived neurons, or increase KDM6A levels in neurons from males. Increasing KDM6A expression in male mice led them to be more resilient to the effects of amyloid beta plaques.
The scientists also looked at public databases of gene expression studies through which they discovered a particularly active variant of KDM6A that is present in about 13 percent of women and seven percent of men around the world. And since women have two X chromosomes, they have a higher chance of carrying at least one copy of the variant.
To explore the role of this variant, the researchers looked at long-term studies involving elderly people, many of whom already had mild cognitive impairment, finding that women with one or two copies of the variant experienced slower progression towards Alzheimer’s. It is unclear whether this is also the case for men who have the variant as there were not enough males in the study to make any conclusions.
The gene expression studies also revealed that women with Alzheimer’s generally had more KDM6A protein in their brains than men with the disease. The studies also showed higher levels of the protein in brain regions that are damaged early in Alzheimer’s. The researchers suggested that neurons in these areas may produce more of the protein to protect against the disease, although this was based on analyses that only showed associations, not causative effects.
Genetic Sex Differences in Disease
While gender differences in diseases like Alzheimer’s have been acknowledged, not much is known about how genetic sex differences may drive disease mechanisms differently in men and woman.
Jennifer Yokoyama, PhD, an associate professor of neurology at the UCSF Memory and Aging Center and member of the Weill Institute, who analyzed the KDM6A variant in the new study, noted that, “Because the X and Y chromosomes are hard to compare to one another, the big genome-wide association studies have all been done on non-sex chromosomes. Perhaps our study will highlight the fact that there could be something pretty interesting on the X chromosome after all.”
Dubal is optimistic about the new research findings from her group, saying that, “Finding this protective mechanism opens the possibility that there may be new therapeutics that could be derived from the X chromosome.”