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A new study suggests researchers may have pinpointed a primary reason why women are more susceptible to Alzheimer’s disease than men, which could lead to breakthrough treatments. MoMo Productions/Getty Images
  • A new study may explain why women are more prone to Alzheimer’s disease.
  • The authors noted that female brains show increased levels of an enzyme that triggers the greater accumulation of the tau protein responsible for the buildup of protein clumps found in Alzheimer’s patients.
  • Authors say the study is not a reason for alarm but a potential breakthrough that could inform the development of pharmaceuticals to protect people, particularly women.

Researchers may have made a major breakthrough in explaining why more women get Alzheimer’s disease than men.

Scientists from Case Western Reserve University have noted that female brains express higher levels of a specific enzyme known as ubiquitin-specific peptidase 11 (USP11).

USP11 works to remove a small protein tag called ubiquitin from proteins, including tau protein.

Normally, ubiquitin targets a protein to be degraded. However, when ubiquitin is removed, this is no longer the case, and proteins can accumulate.

As such, the result of higher levels of USP11 expression is that women have higher accumulations of the tau protein that triggers the development of the toxic buildup of protein clumps, a hallmark of Alzheimer’s disease.

As a result, women have higher accumulations of the tau protein that triggers the development of the toxic buildup of protein clumps, a hallmark of Alzheimer’s disease.

Scientists have known for years that women are diagnosed with Alzheimer’s at a higher rate than men. Alzheimer’s Association estimates that about two-thirds of Alzheimer’s patients are women. Previously, scientists hypothesized that this was because women generally live longer.

“The risk of Alzheimer’s increases with age, and women tend to live longer than men,” said Nikhil Palekar, MD, the director of the Stony Brook Center of Excellence for Alzheimer’s disease and director of the Division of Geriatric Psychiatry.

But Palekar says scientists have also long wondered if there were other factors in play and believes this new research could help provide answers. Another expert agrees.

“This is a cutting-edge finding,” Shae Datta, MD, the co-director of NYU Langone’s Concussion Center and director of cognitive neurology at NYU Langone Hospital—Long Island. “We’ve known for some time there is a 1.7 times higher likelihood of women having higher tau burden and increased incidence of Alzheimer’s, and now we potentially know why.”

But for the layperson, these findings, published in Cell, may alarm and confuse people. Experts shared more on the study — what it tells us, what it doesn’t, and how individuals can lower their Alzheimer’s risk.

The researchers were not expecting to find a potential reason for the increased risk of Alzheimer’s disease in women, says David Kang, PhD, the Howard T. Karsner Professor in Pathology at the Case Western Reserve School of Medicine and co-senior author of a study published. Initially, the goal of the study was to run an objective screen to identify enzymes that would remove ubiquitin from the tau protein.

Why? Because the presence of ubiquitin on tau is regulated by a balanced system of enzymes that either add or eliminate the ubiquitin tag, Kang explains. If this process malfunctions, patients can build up the abnormal accumulation of tau found on the brains of Alzheimer’s patients.

Kang says he and the team were surprised to find that USP11 was located on X chromosomes (of which biological women have two) even in women without dementia.

“Typically, one of the X chromosomes is more or less inactivated in women…but there is 10 to 20% of genes in the X chromosome that can escape this inactivation,” Kang says. “USP11 happens to be one of them.”

When researchers genetically removed USP11 in mice, the indication was that it could protect females against tau accumulation and cognitive decline.

In simpler terms, having two X chromosomes increases the levels of an enzyme that causes protein aggregation in the brain, which leads to Alzheimer’s,” Datta says, adding that inhibiting USP11 could help lower women’s increased risk for Alzheimer’s.

Though women may be alarmed by the study, Kang believes it’s cause for hope.

“We already knew that women were affected more by Alzheimer’s than men,” he says. “We need to know what the cause is. If you don’t know the cause, you can’t do anything about it. This study…is actually pinpointing a cause. Now, we have an opportunity to do something about this.”

Kang cautioned that the animal model used by researchers might not fully translate to humans.

Datta says that these treatments may also be able to assist individuals with other diseases triggered by tau buildup like:

  • multiple system atrophy (MSA)
  • corticobasal degeneration
  • frontotemporal dementia
  • chronic traumatic encephalopathy (CTE)

Palekar also cautions that, though women are more susceptible to Alzheimer’s, their biological sex is not the only risk factor. Others include:

  • brain inflammation
  • age
  • genetics
  • hypertension
  • high cholesterol
  • diabetes

Palekar and the National Institutes of Health say that Alzheimer’s can run in families, though it’s not a guarantee.

Though scientists have yet to pinpoint an exact gene that is directly responsible for triggering late-onset Alzheimer’s disease, the NIH and Palekar note that a person with a genetic variant of the apolipoprotein E (APOE) on the 19th chromosome has a higher risk of Alzheimer’s disease.

This gene helps make the protein that carries fats in the bloodstream.

Additionally, conditions like diabetes and high blood pressure can affect the brain.

“Diabetes, high blood pressure and high cholesterol decrease blood flow to the brain by narrowing the blood vessels, and that can also be associated with Alzheimer’s,” Palekar says. “So, we don’t want to hang our hat on tau.”

People cannot control every aspect of their susceptibility to Alzheimer’s, including biological sex and genetics.

“At this stage, there is no magic bullet,” says Laurence Miller, PhD, a clinical and forensic psychologist and adjunct professor at Florida Atlantic University. “Generally positive health practices are beneficial for both brain and body.”

Palekar agrees that Alzheimer’s can’t be prevented entirely, but he wants patients to feel empowered to do what they can to lower their risk, regardless of their biological sex or family history.

“You have a lot you can do,” he says. These measures include:

  • exercise
  • taking medication and seeking treatment to control conditions like diabetes and cardiovascular disease
  • diet
  • social interaction
  • keeping the brain active through work, games, and puzzles

“There is growing evidence that exercise increases overall cardiovascular fitness and brain oxygenation may have a beneficial preventive effect,” Miller says.

Indeed, a 2020 literature review indicated a link between physical activity and a lower risk of Alzheimer’s development.

Palekar suggests logging 150 minutes of moderate-intensity exercise per week, which breaks down to 30 minutes of activity five times per week.

This is also in line with the Physical Activity Guidelines for Americans developed by the U.S. Department of Health and Human Services

A 2015 study of more than 900 participants ages 58 to 98 indicated that following a MIND diet, a hybrid of the Mediterranean and DASH diets, could reduce cognitive decline.

These diets prioritize lean proteins, produce, and healthy fats like olive oil and de-prioritize ultra-processed foods, sugars, and salt.

A 2018 literature review indicated that a growing amount of data suggests feeling isolated can up the risk of Alzheimer’s as well.

Also in 2018, a small study of 100 cognitively-healthy adults over 50 suggested doing jigsaw puzzles could lower the reduction of cognitive abilities over the long term.