Alzheimer's: Sex hormones linked to development of disease

• Approximately 32 million people worldwide have Alzheimer’s disease.
• About two-thirds of all Alzheimer’s cases are in women.
• Researchers from the University of Western Ontario have found female sex hormones play a significant role in how Alzheimer’s disease manifests in the brain.

In a new study, researchers from the University of Western Ontario found that female sex hormones play a significant role in how Alzheimer’s disease manifests in the brain.

The study appears in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

About 32 million people globally live with a type of dementia called Alzheimer’s disease. Of that number, about two-thirds are women.

Although researchers have some theories about why women are more likely to have Alzheimer’s disease than men, the underlying biological reasons remain unknown.

Why are women more likely to develop Alzheimer’s disease?

There are a few reasons why researchers believe women are at a higher risk for Alzheimer’s disease than men.

The first is longevity, as women tend to live longer than men. In high-income countries, women tend to live 5.2 years more than men and 3.8 years more in low-income countries.

Another factor may be genetics. A study published in October 2022 identified a specific gene on the X chromosome that enhances the accumulation of tau protein in the brain. Because females have two X chromosomes, they may have a higher likelihood of having higher levels of tau protein in the brain, which is considered one of the main causes of Alzheimer’s disease.

And scientists also believe women may be more prone to developing Alzheimer’s disease because of different hormones. Research in mice published in March 2022 discovered the follicle-stimulating hormone (FSH) — levels that rise during perimenopause — are linked to Alzheimer’s risk.

Research presented in 2023 found menopausal women who experience frequent hot flashes during sleep had a higher risk for Alzheimer’s disease.

How female sex hormones affect Alzheimer’s development

Medical News Today spoke with Dr. Vania Prado, professor in the Departments of Physiology, Pharmacology, Anatomy, and Cell Biology at Schulich School of Medicine & Dentistry and scientist at Robarts Research Institute at the University of Western Ontario, and senior author of this study.

Dr Prado said the team decided to examine the possible role of female sex hormones in the development of Alzheimer’s disease because of the chemical changes in the brain that can affect and contribute to amyloid pathology — one of the hallmarks of Alzheimer’s disease.

“One of the important contributors for regulating early pathology are brain cells that secrete acetylcholine,” Dr. Prado explained to MNT. “There is evidence that these brain cells can function differently and they also respond to sex hormones, including estradiol. We knew that from the start.”

“When we examined the relationship between acetylcholine and Alzheimer’s pathology, we found that male and female mice had different responses.

However[,] men and women with Alzheimer’s presented a similar profile. Thus the question became why there are these differences between mice and humans? Sex hormones, because of the age we normally use mice, became the prime suspect.”

– Dr. Vania Prado

Can estradiol affect ‘toxic’ amyloid buildup in the brain?

For this study, Dr. Prado and her team focused on the female sex hormone estradiol, which helps maintain a woman’s reproductive system and plays a significant role in the maturation and release of eggs during the menstrual cycle.

According to the researchers, the cholinergic neurons that produce acetylcholine — which is essential for normal memory and cognition — are vulnerable to damage from beta-amyloid accumulation in the brain that’s linked to Alzheimer’s disease.

Through various tests and image analysis on a mouse model of male and female mice and brain scans of older humans, the researchers found that when estradiol was present, the relationship between acetylcholine and toxic amyloid was lost.

But when sex hormones were eliminated, the relationship was connected, potentially increasing Alzheimer’s pathology. This is especially of note, the researchers said, as levels of estradiol decrease in postmenopausal women.

“We were surprised that in female mice the response was very different than male mice and different than humans, both men and women. The difference was likely because of female hormones, which are likely low in women with Alzheimer’s.”

– Dr. Vania Prado

As for how estradiol may affect the build-up of beta-amyloid protein in the brain, Dr. Prado said that is still not fully understood.

“There is evidence that low levels of estradiol may affect how immune cells respond to amyloid in the brain,” she continued. “There is also evidence that loss of estradiol increases amyloid pathology.”

Insights on sex-specific factors and Alzheimer’s

Medical News Today also spoke with Dr. Verna Porter, a neurologist and director of the Dementia, Alzheimer’s Disease, and Neurocognitive Disorders at Providence Saint John’s Health Center in Santa Monica, CA, about this study.

As a doctor treating female patients at high risk for Alzheimer’s disease, she said she found this study to be one of great interest.

“The findings presented in the study provide valuable insights into the role of sex-specific factors, particularly the impact of estradiol and cholinergic signaling, in Alzheimer’s disease.

Understanding these factors can significantly influence how I approach risk assessment and discussions with female patients, especially those in the perimenopausal age range. In future discussions with my female patients, I would use these findings to provide a more personalized and informative approach to Alzheimer’s risk assessment and management.”

– Dr. Verna Porter

Dr. Porter said these findings may also lead to a need to emphasize the importance of considering the patient’s hormonal status, including their menopausal stage and the role of estradiol, when assessing their Alzheimer’s risk.

“This would be particularly relevant for perimenopausal women, as the study suggests that estradiol may impact the relationship between cholinergic signaling and amyloid pathology,” she added.

“For those in the perimenopausal age range, we should continue to stress the importance of monitoring cognitive health and considering lifestyle modifications, such as maintaining cognitive stimulation and a healthy diet, which have been associated with a reduced risk of Alzheimer’s disease,” Dr. Porter said.

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