The Brain’s Blood Vessels May Be Driving Cognitive Decline in Women

Before 1993, researchers seldom included women in clinical trials. And yet, women have dramatically different risk of health conditions than men do. For example, women are twice as likely to develop Alzheimer’s disease. But as the sex make-up of trials has become more diversified, some new revelations have come to light that could help explain discrepancies like this one. One intriguing difference that could be pivotal for women’s brain health: blood vessels.

Blood vessels are essential for the brain, delivering oxygen and nutrients that power the brain cells. High blood pressure and other cardiovascular diseases, which are known risk factors for dementia, damage those blood vessels and in turn starve the brain. Now, scientists are investigating if the way these blood vessels age differently between genders could explain why women’s outsized Alzheimer’s risk.

Scientists don’t yet know why women are more likely to develop Alzheimer’s or other forms of dementia. In a new study published in Science Translational Medicine, researchers measured blood biomarkers of angiogenesis — the ability of blood vessels to grow, replace damaged vessels, and maintain healthy function — to see whether they reflected how well participants scored on cognitive tests. The levels of angiogenesis biomarkers in women correlated to these test scores — while younger women with high levels of biomarkers scored better on cognitive tests, later in life, women with the same high levels of biomarkers tended to do worse on these tests. In men, the levels of these biomarkers didn’t show any correlation. 

“This [study] is beginning to get at some of the pathological changes that can occur that put women’s brains at risk of degeneration and, ultimately, dementia,” Dr. Fanny Elahi, a neurologist and associate professor at Mount Sinai who led the study, told Being Patient.

Zeroing in on new biomarkers of cognitive function

The researchers analyzed data from 435 cognitively healthy older adults aged 40 to 90. The participants provided blood samples and underwent brain imaging and cognitive tests once a year for six years. 

From the blood tests, the researchers zeroed in on seven protein biomarkers of angiogenesis and tracked how they changed over time. Based on the levels of these biomarkers, they could predict whether someone’s blood vessels were actively undergoing angiogenesis. 

In women, this process signaled better cognitive function up until the age of 75. Afterward, this process correlated with worse scores on the cognitive tests. Elahi called the results “puzzling” and added that “we need to understand what’s [behind] the physiological shift” in the meaning of these biomarkers. 

Katerina Akassoglou, a professor at the University of California San Francisco, who was not involved in the study, told Being Patient that taking a closer look at biomarkers of abnormal blood vessel function “may pave the way for novel plasma biomarkers [which were tested in this study] and combination therapies for maximum therapeutic benefit in Alzheimer’s disease and other dementias.”

Finding new treatments for women

Even though many clinical trials now include women, scientists are less likely to receive funding for diseases that affect more women than men, or studies that focus on women’s health. 

Elahi said that although women are included in studies today, many researchers don’t check for gender-specific effects in their results. 

Understanding why angiogenesis could affect brain function and developing treatments to reign in this physiological process could also impact other diseases that primarily affect women, like breast cancer, preeclampsia, and autoimmune diseases. 

Elahi’s lab is using research into angiogenesis as a jumping-off point to develop and repurpose existing drugs to target some of the biomarkers of this process. “Maybe we’re tapping into biology that’s really relevant to Alzheimer’s disease or other disorders of brain aging for which women have a higher risk and propensity,” said Elahi. 

If successful in the lab, these drugs could then be tested in clinical trials to see if targeting angiogenesis could treat dementia, as well as other conditions in women.