Like many labs in the early stages of the COVID-19 pandemic, Yale School of Medicine’s Clinical Neurosciences Imaging Center temporarily stopped bringing in patients for research. Like many researchers without new subjects to scan, Dr. Carolyn Fredericks and her team took advantage of the pause by taking a closer look at publicly available data.
As a clinician-scientist with a long-standing interest in studying neurodegenerative disease, Dr. Fredericks focused her attention on how brain circuitry changes in women and men as they age. What she and a research associate found surprised her.
Distributed across the brain is a circuit known as the default mode network (DMN), important for episodic memory and what is known as self-referential processing, such as mulling over previous conversations. Studies have shown that this network is specifically targeted by Alzheimer’s Disease (AD).
Dr. Fredericks was intrigued to discover that as women age, this circuit begins to look more like people who are at higher risk for developing AD, even if they show no cognitive symptoms. This circuit in the brains of men, on the other hand, tends, over time, to look more like what has been observed in past studies of brain aging.
“The back parts of the DMN seem to be more connected to the rest of the DMN in women than men,” said Dr. Fredericks, an assistant professor of neurology and a clinician specializing in neurodegenerative disorders. “And this is also something we’ve seen in people with preclinical Alzheimer’s disease or an increased genetic risk for the disease. But nobody has explored the impact of this sex difference.”
Now, with a grant from Women’s Health Research at Yale, Dr. Fredericks is employing a cutting-edge neuroimaging technique to do just that.
“It’s very easy to see that women have more cases of Alzheimer’s disease than men,” Fredericks said, noting that two-thirds of all people affected in our country are women. “But it’s more complicated to understand why women are at increased risk.”
Examining a Genetic Variant
Women on average live longer than men and so have greater incidence of age-related dementias. In addition, gender-based factors can influence cognitive decline. For example, women tend to have less access to education, physical activity, stimulating employment, and other social determinants of health shown to protect against the cognitive effects of aging.
However, research has also shown a growing biological basis for the different rates of AD in women and men. For example, the disease often advances more quickly in women than men. Dr. Fredericks’s new study focuses on the genetic variant that is more likely to affect the development of AD in women than men.
This variant, known as the APOE-ε4 allele, is a mutated form of the apolipoprotein E (APOE) gene on chromosome 19, which helps to create a protein involved in carrying cholesterol and other types of fat through the bloodstream. Everyone inherits one APOE allele from each parent. For women who carry one copy of the APOE-ε4 variant, the risk of developing Alzheimer’s disease can be as high as 12 times as great as someone without this variant. But men with one APOE-ε4 allele have little or no increased risk.
Researchers estimate that 25% of the U.S. population possesses at least one APOE-ε4 allele, and little is known about what might be happening inside the brains of women with this variant to make them so much more susceptible to developing Alzheimer’s disease.
A High-Powered Model to Make Predictions
Dr. Fredericks is using an extensive database of individuals who have a large buildup in their brains of a protein associated with Alzheimer’s disease but no cognitive symptoms. With data from magnetic resonance imaging (MRI) and abundant health information, her team will apply a new technique developed at Yale called connectome-based predictive modelling to identify the specific signature of abnormal brain network connectivity in women and men who carry the APOE-ε4 allele.
This technique divides the brain map into about 268 clusters based on the type of functions carried out in each cluster. The researchers then create a 268 x 268 matrix showing the strength of the connection between each pair of clusters and examine which connections predict the outcomes under investigation. In this study, they are looking to see if the patterns predict the presence of the APOE-ε4 allele as well as short-term memory performance and then comparing the results for women and men.
Based on the size of the dataset and the power of this technique, the researchers anticipate being able to apply what they learn in one group of individuals to predict an outcome in an entirely different set of individuals. For example, if they notice that women with a particular pattern of brain connections have the APOE-ε4 allele, they expect to see that those same brain connections predict the presence of the APOE variant in another randomly assembled group of people. If, as hypothesized, a specific set of connections only appears in women and not men, they can begin to investigate the functional impact of APOE-ε4 on the brains of women who develop Alzheimer’s disease and create new opportunities for therapies aimed at a specific molecular or anatomical target.
While still early in the long process of exploring one of the most devastating diseases within the most complicated biological structure on earth, Dr. Fredericks expressed great hope for this new technique.
“As we move toward an era of tailoring medicine to the individual, we need to recognize there is not always a one-size-fits-all cure,” she said. “Pathology can move differently, and genes can impact health differently for people depending in part on their sex or gender. I think the future of understanding Alzheimer’s disease is looking very hopeful. But understanding the specific mechanisms of the disease for individuals will be important to target treatments the right way.”