One of the biggest unanswered questions about Alzheimer’s disease is why it affects more women than men. Existing theories—that women live longer, have stronger immune systems, and experience a higher rate of autoimmune diseases—don’t fully explain the fact that almost two-thirds of Alzheimer’s patients in the U.S. are women.
Now, results from a new study suggest that the X chromosome itself may play a role, too. Researchers from Case Western Reserve University found that the instructions to build an enzyme called USP11, which plays a role in the development of neurodegenerative diseases, resides on the X chromosome. Recall from your high-school biology class that females possess two copies of the X chromosome, while males only possess one, and you can see why the implications for Alzheimer’s are big.
The new study, published Tuesday in the journal Cell, suggests that a new promising avenue for Alzheimer’s treatment could be drugs that lower levels of USP11 or erase it from the genome entirely.
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“USP11 is an enzyme, and enzymes can traditionally be inhibited” with drugs, pathology researcher and study co-author David Kang said in a press release. “Our hope is to develop a medicine that works in this way, in order to protect women from the higher risk of developing Alzheimer’s disease.”
The researchers found that reducing the amount of USP11 made in both human cells and mice caused the levels of a protein called tau to decrease markedly. In healthy brains, tau helps stabilize neurons in the brain, but in dementia and Alzheimer’s disease, an abnormal form of tau builds up and starts sticking together. These threads become convoluted tangles that make it harder for neurons to communicate with one another in brain regions that are important for memory.
Sometimes, when a person has two X chromosomes, only one of their X-linked genes makes proteins per cell. However, the Case Western team found that both copies of USP11 remained active—meaning females produce more USP11 than males.
The authors note that future studies in human cell lines, post-mortem brains, and eventually living participants will be needed to solidify the link between USP11 and Alzheimer’s, since mouse models are not perfect mimics of the disease. Moreover, there may be even more X-linked enzymes and other proteins that play a role in Alzheimer’s susceptibility and progression. Studies that zero in on these causes and begin to test solutions may usher in a new class of treatments that stop Alzheimer’s development at its source, improving millions of lives.
