Far more women develop Alzheimer’s disease than men. Scientists may have finally figured out why

CLEVELAND — Far more women are diagnosed with Alzheimer’s disease than men. In fact, close to two-thirds of the over five million Americans living with the most common form of dementia are female. The reasons behind this gender disparity are still unknown, but one prominent theory states women exhibit significantly higher depositions of the tau protein in their brains.

Now, new research from Case Western Reserve University’s School of Medicine is lending further support to that theory. Scientists conclude that the female brain displays a higher expression of a certain enzyme compared to males, resulting in greater accumulation of the tau protein. They posit this discovery may help develop new medicines to treat dementia.

The tau protein causes the formation of toxic protein clumps found inside the brain nerve cells of Alzheimer’s disease patients. The enzyme in question, meanwhile, is called ubiquitin-specific peptidase 11 (USP11). This enzyme is also X-linked, which means it is found in genes on the X chromosome, one of the two sex chromosomes in each cell.

“We are particularly excited about this finding because it provides a basis for the development of new neuroprotective medicines,” says study co-author David Kang, a professor in pathology at the medical school, in a statement. “This study also sets a framework for identifying other X-linked factors that could confer increased susceptibility to tauopathy in women.”

“When a particular tau protein is no longer needed for its nerve cell’s function, it is normally designated for destruction and clearance,” Kang continues. “Sometimes this clearance process is disrupted, which causes tau to pathologically aggregate inside nerve cells. This leads to nerve cell destruction in conditions called tauopathies, the most well-known of which is Alzheimer’s disease.”

Eliminating excess tau begins with the addition of a chemical tag called ubiquitin to the tau protein. Ubiquitin’s presence on tau is then regulated by a balanced system of enzymes that either add or remove the ubiquitin tag.

Since dysfunctions in this delicate, balanced process can lead to the abnormal accumulation of tau seen in Alzheimer’s disease, study authors set out to investigate why this is the case. More specifically, the research team searched for increased activity of the enzymatic system controlling the removal of the ubiquitin tag. Why? Over-activation on that side of the balance may lead to pathological tau accumulation.

“We reasoned that if this could be identified, then it could provide a basis for the development of new medicine that could restore the proper balance of tau levels in the brain,” Prof. Kang explains.

The investigation reveals that women naturally express higher levels of USP11 in their brains than men. Additionally, USP11 levels appear to correlate strongly with brain tau pathology in females but not among males. When the research team genetically eliminated USP11 in a mouse model of brain tau pathology, females were actually “preferentially protected” from tau pathology and cognitive impairment. Males were also protected against tau pathology in the brain, but not nearly as much as females.

Researchers say their findings suggest excessive activity of the USP11 enzyme in females drives increased susceptibility to tau pathology in Alzheimer’s disease. That said, study authors note that animal models may not have totally captured the full spectrum of tau pathology seen in humans.

“In terms of implications, the good news is that USP11 is an enzyme, and enzymes can traditionally be inhibited pharmacologically,” Prof. Kang concluded. “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 study is published in Cell.

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