Sophia_Zhao Neurons, Staff Illustrator

Women suffer from Alzheimer’s disease more often and more severely than men, and yet very little research has been done to find out why. 

A recent Yale study tackling this knowledge gap has found key structural differences that may help explain why women are at a higher risk for Alzheimer’s. 

This study, led by assistant professor of neurology and Women’s Health Research at Yale collaborator Carolyn Fredericks, analyzed differences in an area highly linked to Alzheimer’s: the Default Mode Network. The Default Mode Network is a set of brain regions that interact to put someone in a state of wakeful rest, such as daydreaming, and it is key for short-term memory functions. 

“There’s this whole phenomenon that’s so interesting, where women are at a much greater risk of Alzheimer’s disease than men are,” Fredericks said. “It’s like two-thirds of cases are women, so we got really interested in trying to tease this out.”

When the researchers compared changes in the Default Mode Network over time, they found notable distinctions between male and female brain connectivity. Most significantly, they found that healthy women’s posterior connectivity patterns are similar to those of a preclinical Alzheimer’s patient, which is a potential source of women’s higher predisposition for Alzheimer’s.

To this end, Fredericks and her team scrutinized large, cross-sectional data. They relied on banks of neural scans from the Human Connectome Project-Aging cohort — a National Institute of Health project that aims to map out the human brain. These banks included scans from 595 healthy adults.

With these scans, researchers examined the intrinsic connectivity distribution, an explanatory tool to detect brain tissue connectivity and function. They also used seed connectivity distribution, a tool to measure connectivity patterns for related brain areas such as the Default Mode Network. These tools helped the researchers measure sex differences in the Default Mode Network and the entire brain. 

“We were taking the big data sets from the Human Connectome project and then preprocessing all those, which means [we took] the raw MRI images and then [made] them so that [we] can all put them together and then … divide the brain in different sections and … do a lot of math and statistics,” said Bronte Ficek-Tani, one of the authors of the study.

In the end, the researchers found key differences between men and women in their Default Mode Network connectivity over the course of their lives. One such difference was that women had significantly higher network connectivity in major posterior nodes of the Default Mode Network over time.  

“That pattern of relative posterior connectivity has been seen before in people with preclinical Alzheimer’s disease,” said Fredericks. “So when I saw it and discovered it in healthy women, I was immediately struck by it.”

The similarity of posterior connectivity between women and patients with Alzheimer’s suggests that there is a noteworthy difference between the biological sexes that results in women being more prone to Alzheimer’s. Additionally, the most notable differences in male and female connectivity came around the ages that menopause tends to begin in women. 

However, Fredericks and her team acknowledged that there was room for improvement in the study. The study relies on a large cross-sectional healthy group of adults. The use of this data, according to Fredericks, fails to account for long term changes over an individual’s life. 

Nevertheless, Fredericks views this as both a strength and weakness of the study.

“This data set is huge and everyone in it is healthy, so that’s both useful because it shows us a huge section of the lifespan and what we would expect to see in healthy people across that life span,” Fredericks said. “If you think about it, a cognitively healthy 90-year-old is very different from a cognitively healthy 35-year-old. 5-year-olds could go on to develop Alzheimer’s Disease at 70, and we would never know that.”

Even accounting for these limitations, the study accomplishes its goal of reducing the gap in the scientific understanding of sex differences in Default Mode Network development. For Fredericks and her team, this study was an attempt to set a foundation for future research. 

All the researchers spoken to by the News noted that with time, improved data sets will be released that can account for longitudinal data. As a result, they said, the findings will only become more precise. 

Fredericks plans to continue her research in this field by studying people who “have Alzheimer’s topology but their brains don’t have symptoms yet.”

By continuing to focus on sex differences, we can better tailor clinical tools,” Horien wrote. “Instead of a ‘one-size-fits-all’ approach for an ‘average’ patient, we can start to understand how sex differences impact biology, and how this biology shows up in the clinic.”

Alzheimer’s Disease was first described by scientists in 1906.

Carlos Salcerio covers the Yale School of Medicine and the Yale School of Nursing for the SciTech desk. Originally from Cuba, he is a prospective pre-medical student majoring in Molecular Biophysics and Biochemistry in Jonathan Edwards College.