Nov. 10, 2022 – Of the more than 6 million Alzheimer’s patients in the United States age 65 or older, nearly two thirds are women. New study could help explain the gender difference — and provide clues to new treatments to help patients of both sexes fight back.
Researchers at Case Western Reserve University zeroed in on a gene called USP11, which was found on the X chromosome. People assigned female at birth have two X chromosomes, while people assigned male at birth have one X and one Y. So while all men have one copy of USP11, women have two.
The body’s waste collection system
To understand the role of USP11 in the body, imagine that you are on the sidewalk of a bustling city. Just like the inhabitants of the buildings, our brains create waste that must be hauled away. If the waste was left on the pavements without removal, it would pile up, seep into roadways, disrupt lives and become toxic to the environment.
In the brain, one of the waste products is a protein called tau. Too little tau can damage neurons, explain researchers David Kang, PhD, and JungA “Alexa” Woo, PhD, who led the study. But too much will be toxic and can lead to neurodegenerative diseases like Alzheimer’s. (Actually, new research suggests that testing for changes in tau may someday help doctors diagnose Alzheimer’s earlier.)
To control tau, your brain uses regulatory proteins called ubiquitin to “mark” or signal to the body that extra tau should be removed. In an urban analogy, ubiquitin is like attaching a sign to a garbage bag, telling the garbage collector to pull the bag away.
The role of USP11 is to provide instructions for making an enzyme that removes the ubiquitin tag to maintain homeostasis. (You don’t want to get rid of all the tau protein. Justsomeof it.) But if too much of the enzyme is present, too much tau is released – and not enough of it is cleared.
“Our study showed that USP11 is higher in females than males in both humans and mice,” says Kang. “It’s already true before the dementia started.” But when someone has Alzheimer’s disease, USP11 is much higher – regardless of gender.
The study adds a mounting evidence showing that women may be more sensitive than men to higher levels of tau, which may explain why women are affected by the disease more often than men.
But what if there was a way to “turn off” or turn off the USP11 gene? Could it help prevent Alzheimer’s? And could it be done safely?
What happened when the gene was eliminated?
To examine these questions, researchers used a gene manipulation approach to completely delete the USP11 gene in mice. They then examined the mice for changes. Outcome? The mice seemed fine.
“The mice bred well. Their brains looked good,” says Woo.
It would not be possible – or ethical – to remove genes from humans. But when a disease condition renders a particular gene unhelpful, that gene can be partially shut off or the gene’s expression can be reduced with drugs. In fact, drugs that target enzymes are common. Examples include statins for cardiovascular diseases or HIV treatments that inhibit protease enzymes.
“If we can identify some type of drug that would inhibit USP11, our study suggests that it would be well tolerated and beneficial in women,” says Woo.
Kang also warns that the process of creating such a treatment will take at least 10 to 15 years. The researchers say they want to shorten the timeline and plan to study existing FDA-approved drugs to see if any might work to target USP11 gene activity — and hopefully bring new Alzheimer’s treatments sooner.