Alzheimer's and X chromosome: Why women are more at risk

• X chromosome inactivation occurs on one X chromosome in all human females’ cells, but some genes escape this inactivation and are expressed anyway.
• Whether or not one of these genes influences the likelihood of developing tau tangles, which are present in the brains of people with Alzheimer’s disease, was the focus of a new study by researchers at Case Western Reserve University in Cleveland.
• Scientists have proposed a potential underlying mechanism behind why women are more likely to develop Alzheimer’s disease than men.

Women are nearly twice as likely as men to develop Alzheimer’s disease, according to the Centers for Disease Control and Prevention (CDC), but there is little understanding of why exactly this is.

The condition is the most common form of dementia, and it affected 5.8 million Noth Americans in 2020. As the population ages, the incidence is set to increase, and it is expected it is going to affect 14 million people by 2060 in the United States alone.

This means that discovering the reasons behind why and how Alzheimer’s develops is increasingly important so that researchers can set new drug targets and doctors can make early interventions.

Researchers have identified some genetic variants that are linked to an increased or decreased risk of Alzheimer’s disease, including some that only exist in females.

There have been other attempts to understand the reasons behind why Alzheimer’s, but not other forms of dementia, is more prevalent in females, and hypotheses around the effect of menopause, longer life expectancy, and the immune system have been proposed.

Silencing the X chromosome

All human females have a pair of X chromosomes. Early during embryo development one of the X chromosomes will be inactivated, and all cells in the female human body have just one X chromosome that is transcriptionally active.

This helps prevent the overexpression of genes that are present on both X chromosomes. There are a couple of genes that escape this X chromosome inactivation, and the reason and impact of this are not entirely understood, as a recent review has outlined.

Now, a recent study by researchers at Case Western Reserve University, Cleveland, has proposed that one of the genes that escape X chromosome inactivation could contribute to an increased risk of developing Alzheimer’s in females. It appears in Cell.

Studying tau protein accumulation

People with Alzheimer’s disease have tangles of a protein known as tau in and around the nerve cells in their brain which disrupts cell signaling.

The misfolding that leads to the aggregation of these proteins is not only present in Alzheimer’s but also in some other neurodegenerative conditions. Tau forms in healthy neurons but is cleared by the action of enzymes called kinases, which stops it from building up normally.

Researchers believe that mechanisms that disrupt this process could lead to the development of accumulations of tau and the amyloid plaques that are characteristic of Alzheimer’s disease.

Previous research has shown that women have greater tau deposits in their brains before they develop Alzheimer’s symptoms, and some experts think this could be a foundational event for the disease.

Researchers proposed that the ubiquitin-specific peptidase 11 (USP11) protein, the gene for which is expressed on the X chromosome and evades X chromosome inactivation, removes a molecule from the tau protein which makes it more likely to tangle. This leads to tau accumulation.

To test this hypothesis, they first used HeLa cells — so named after Henrietta Lacks, the woman whom the initial set of cells came from — which they had knocked the USP11 and USP13 proteins out of. In doing so, they observed there were lower levels of tau proteins in them.

Other experiments included looking at the brain tissue from deceased patients with Alzheimer’s disease, as well as brain tissue from patients who had not had dementia to determine whether USP11 production is deregulated in humans with Alzheimer’s.

They found that quantities of the USP11 protein were 9.5-fold higher in the brain tissue of Alzheimer’s disease patients than it was in people who did not have dementia.

Finally, researchers created mice with the gene that codes for USP11 knocked out of their genome and discovered that these female mice had a lower amount of tau in the brain.

What does this mean?

These observations were “of great interest to the field,” said Prof. Julie Williams, director of the Dementia Research Institute at Cardiff University in the United Kingdom, whose work focuses on discovering gene loci and variants that make a person more likely to develop Alzheimer’s disease.

She told Medical News Today in an interview:

“I would not go far as saying it’s causing the sex difference, but it may be contributing, but there’s a bit more work that needs to be done to really stand that up. But it is a very interesting and novel finding.”

She also pointed out that many previous genome-wide association studies done to determine which genetic variants might increase the risk of developing Alzheimer’s had not looked at the USP11 gene, and “that is work that needs to be done.”

Researchers have proposed that the increased risk of Alzheimer’s disease comes not only from the deregulation of tau protein clearance as a result of higher levels of USP11 protein in females, but also as the USP11 protein regulates estrogen-induced estrogen receptor activity.

More research in humans needed

The lack of replication of results in humans was a limitation of the paper that the authors noted.

Prof. Bart De Strooper, director of the UK Dementia Research Institute at University College London, told MNT that “[i]t should be noticed that the evidence [is] largely gathered in a preclinical setting, in models of the disease such as cell cultures and mouse models, but that the experiments are sound and indeed support the overall conclusions of the paper.”

“I agree with the conclusions of the paper,” he commented, “and I would say that this work deserves further follow-up by drug developers to see whether the X-linked ubiquitin-specific peptidase can be targeted in the context of Alzheimer’s and frontotemporal disease.”

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