Alzheimer’s disease is a progressive neurological disorder, causing problems with memory, thinking, and behavior. It is the most common form of dementia, affecting an estimated 6.7 million Americans aged 65 and older, and is the sixth leading cause of death in the nation. Two-thirds of those with Alzheimer’s disease in the U.S. are women, yet having longer life expectancy does not fully explain this high prevalence.

Carolyn Fredericks, MD, has dedicated her research career to understanding risk of and resilience to Alzheimer’s disease and is working to determine why this disorder is so much more common in women than men. Motivated by a personal connection to the disease, a curiosity about how brain circuits function, and her commitment to cognitive neuroscience, Fredericks has made an impact in uncovering new knowledge to address this disease.

In 2022, Fredericks was awarded a Pilot Project Program grant from Women’s Health Research at Yale to determine the relationship of a known genetic risk factor for Alzheimer’s disease to brain circuitry in women compared with men. Her project is now complete, and this article explores her findings.

“Funding from Women’s Health Research at Yale was transformational for my research. At the time, I was able to hire my first post-baccalaureate research associate, which helped me establish and grow the Fredericks Lab. Having this kind of funding is license to investigate a promising scientific idea and examine the influence of sex on a disorder that we know is more common in women,” says Fredericks.

Helpful Definitions

Alzheimer’s Disease: A type of dementia that affects memory, thinking, and behavior. Symptoms eventually interfere with daily tasks, such as dressing and eating.

Dementia: An umbrella term that describes a collection of symptoms including a decline in memory, reasoning, and other thinking skills that are driven by specific diseases, including Alzheimer’s, Lewy Body disease, vascular disease, and more. The term “dementia” simply means that those symptoms are impactful enough that they interfere with a person’s day-to-day life.

Allele: A version of a gene that can exist in different forms. Each gene in one’s DNA typically has two copies, one inherited from each parent.

Tau: A protein that helps maintain the structure of nerve cells, essential for proper functioning. Along with the protein amyloid, tau is harmful in Alzheimer’s disease when it abnormally folds and forms tangles that interfere with neuronal function.

Amyloid: A term for proteins that misfold and form deposits in tissues or organs. In Alzheimer’s disease, amyloids form plaques in the brain, contributing to neuronal damage.

Synaptic Density: The number of connections between neurons – or synapses – within a given area of the brain or nervous system. Synapses are essential in transmitting information across the brain and nervous system.

Brain Edge: A link or connection between two regions of the brain, which can be either structural or functional.

Fredericks’s Hypothesis

It is well documented that women who carry a single APOE-ε4 allele, a mutated form of the apolipoprotein E (APOE) gene on chromosome 19, are at far greater risk of developing Alzheimer’s disease than men with the same risk factor. The allele’s job is to create a protein involved in carrying lipids – fatty compounds that help control what goes in and out of your cells – through the bloodstream. Every person 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 three times greater than someone without this variant.

Fredericks recognized, however, that not enough is known about the impact of the genetic risk factor on brain circuitry in women compared with men. Through her Pilot Project Program grant, she evaluated a large public dataset that included brain scans and APOE test results for more than a thousand individuals who had preclinical Alzheimer’s disease – meaning, they had evidence of Alzheimer’s pathology in their brains but had yet to show cognitive symptoms of Alzheimer’s disease.

Using a technique called connectome-based predictive modeling that allows researchers to visualize communication within the brain, Fredericks and her team aimed to identify aspects of brain connectivity that are associated with the APOE-ε4 allele in women, in men, and in both sexes together. The reigning hypothesis of the project was that the APOE-ε4 allele, which increases lifetime Alzheimer’s risk especially in females, leaves a specific signature of abnormal brain network connectivity in women as opposed to men.

What the team successfully modeled was which parts of the brain had activity that was tightly correlated – meaning areas that were strongly synchronized, working together to achieve an outcome – and how that tightly correlated activity related to how much tau accumulation was in the corresponding regions.

Tau is an important protein in brain health, but when it malfunctions, such as folding onto itself or becoming detached and forming tangles, it contributes to the development and progression of Alzheimer’s disease. Impairments in brain connectivity in Alzheimer’s disease may pave the way for pathological tau to detach and accumulate into twisted tangles, disrupting the structure and function of neurons.

Early Discoveries

Over the two-year investigation, Fredericks and her team successfully developed a method for using functional connections in the brain to model and predict the location of tau in brain networks of individuals with amyloid deposits, or preclinical disease. These findings are currently under review at a leading medical journal.

“We were able to quite accurately predict where tau would be present in someone’s brain – and we were best able to model tau in regions we were not initially expecting,” said Fredericks. “Instead of best modeling tau where it usually accumulates, we were most successful predicting tau levels in the most connected regions, which was a surprising result.”

Building on the promising tau findings, Fredericks, in collaboration with a research team that included Gillian Coughlan, PhD, a neurology research fellow at Massachusetts General Hospital, submitted a grant proposal to the National Institutes of Health to explore the impact of sex on how functional connections impact tau pathology. Specifically, they will examine menopausal timing, hormone replacement therapy, and tau accumulation with a focus on functional connectivity and tau by sex and the impact of specific reproductive health history. The investment made by Women’s Health Research at Yale in Fredericks’s Pilot Project Program grant led directly to the preliminary data for this grant submission.

The Importance of Studying Sex Differences

The Fredericks Lab studies sex as a biological variable in its research and most recently began a collaboration with the Yale Alzheimer’s Disease Research Center to evaluate sex differences in synaptic density and how these too might relate to differences in functional circuits. Work is preliminary, but trends are already emerging that show differences between women and men.

“On the most basic level, we are just starting to learn about sex differences in Alzheimer’s, and yet the effects appear to be profound,” reflects Fredericks. “It may be that, as we move into the era of disease-modifying treatments for Alzheimer’s, some drugs will work better for women than others, and assessing for sex differences hasn’t always been taken into account in study design. As a clinician, when I counsel my patients – the majority of whom are women – about considering a medication to slow progression or potential disease onset, it will be important for me to know whether a new or future drug has been evaluated for efficacy specifically in women.”

Core Discoveries & Lasting Impact

Fredericks’s Pilot Project showed that healthy women over the course of aging, and especially in the decades around menopause, have tighter connections in the posterior areas of the brain than do men. These are areas that are major components of a network traditionally associated with short term memory performance. Tighter brain connections here mean a strong, closely linked, and efficient relationship between different regions of this network, equating to seamless coordination in performing tasks and processes. People with tighter connections tend to do better on cognitive tests such as recalling a list of words. In addition, the team’s models provide evidence that distinct brain edges for men and women predict short-term verbal memory task performance.

Further, they found that default mode network (DMN) edges are more prominent in women’s memory. The DMN is a network of brain regions, including the medial prefrontal cortex, posterior cingulate cortex, and parts of the hippocampus, which are active when a person is at rest, particularly during self-reflection, memory retrieval, and introspection. The team found higher segregation of the DMN in women as compared to men, meaning that women may rely more exclusively on this network during memory performance. This could prove a substantial finding, as similar patterns of higher connectivity in the posterior nodes of the DMN have been seen in people in the earliest, preclinical stages of Alzheimer’s disease.

“We wonder if this is an indication that women’s brains are set up to use these connections more efficiently, but also more intensively, than men’s – sort of like a road that gets more wear and tear. This may be a good thing for the short and medium term, but ultimately that wear and tear in the memory network may allow tau to spread faster in women who develop Alzheimer’s disease,” Fredericks reflects.

Hence, the research persists.