NeuroVoices: Jessica Caldwell, PhD, on Evaluating Brain Regions and Functional Connectivity to Understand Sex Differences in Cognitive Decline


The director of the Women’s Alzheimer’s Movement Prevention Center at Cleveland Clinic discussed new research which looked at the differences in functional connectivity for men and women of older age.

Jessica Caldwell, PhD

Jessica Caldwell, PhD

In 2018, research published by Cieri and Esposito highlighted functional connectivity of the default network as one of the most important and affected networks in Alzheimer disease (AD). Although it has been known that AD is more prominent in women, the reasons for why these disparities exist are unknown.1 Led by Jessica Caldwell, PhD, a study presented at the 2022 Alzheimer’s Association International Conference, July 31 to August 4, in San Diego, California, explored sex differences in several regions of the default network using patients clinically diagnosed as health control, mild cognitive impairment (MCI), and AD.

Caldwell and her colleagues selected 7 regions of interest in the default network, including bilateral angular gyrus (ANG), calcarine (CAL), precuneus (PCUN), medial orbital frontal gyrus, and bilateral middle occipital gyrus (MOG). Using analysis of variance, findings showed significant differences between diagnostic groups in functional connectivity of left ANG-PCUN/CAL and bilateral MOG-CAL. Significant diagnosis by interaction effects were observed in functional connectivity especially at the level of posterior-ventral default network.2

Caldwell, director of the Women’s Alzheimer’s Movement Prevention Center at Cleveland Clinic, sat down as part of a new NeuroVoices to provide greater context on her study, and the major take-home points clinicians should be aware of. She discussed the utility of functional connectivity, overcoming sex differences in AD, and the realistic possibility of creating sex-directed therapeutics.

NeurologyLive®: What was the reasoning for focusing in on the networks you observed?

Jessica Caldwell, PhD: In this study, we selected seven regions that are within the default mode network. The default mode network is a network of regions of the brain that are more active when we are resting rather than when we're engaged in any particular task. Many studies look at functional connectivity, or how regions interact, when the brain is at rest. The regions that we chose were fairly standard in terms of how to break down that network into nodes that have known different functional connectivity and functionality. When we started the study, we were influenced by some studies in the past that have shown that the default mode network changes in a somewhat predictable way in Alzheimer's disease, with a higher activation in the posterior nodes of the network, followed by lower activation. The pattern then propagates forward in the network such that it's almost like a wave of higher activity, and then lower activity that is indicative of the pathology.

Among the findings, what were the most notable take-home points?

To put in context, we're looking at sex differences because women have greater rates of Alzheimer disease and a different pattern of decline when they get diagnosed with AD. Our prior research looked at how women hang on to what we call “memory reserve.” Many women show a pattern where their memory is looking pretty good, even when they have mild cognitive impairment in comparison to men, and then almost seem to fall off this memory cliff between MCI and Alzheimer disease dementia. What we've been looking at is, how do women hang on to that reserve compared with men who have more of a linear decline? Is that their brain structure? Is it their brain function, or in this case, the way their brain default mode, network connectivity actually looks? What we found is consistent with our prior research, which is that women seem to have a pattern of compensation earlier in the disease, where at the level of MCI, their brain is boosting the conductivity and maintaining potentially the memory. But men's brains are not doing that same thing. At the stage of Alzheimer disease, women see a drop-offin the strength of the functional connectivity, whereas men see an increase, almost indicating that men are able to have some compensation at those later stages potentially, where women are not.

What is the value in functional connectivity and how can it help us learn more about Alzheimer disease?

Functional connectivity is a hot topic for a number of reasons. One of those reasons is that it's a measure that can be used across the Alzheimer disease continuum, from people who are healthy all the way and have normal memory to folks with dementia. Because the way that this is measured is just by having an individual lie in the MRI machine, and rest with their eyes open.That's something that even folks with significant cognitive impairment are able to do, whereas sometimes the other types of imaging tasks that might require someone to do a memory test or so on, are difficult for someone with cognitive impairment to engage in at the same level. We're able to get information about how the brain is functioning without putting a major demand on the person with dementia, for example.

Is it possible to envision future therapeutics directed solely for women?

That kind of precision medicine, including directing medical targets toward women and men specifically, is certainly the goal. I don't think we're there yet, but I think that work like mine, points to the fact that it may be more important to engage women either in trials or in preventative approaches, even earlier than men. That’s not to say it's not important for everyone, but we're seeing this different trajectory. If we're targeting therapy and we want to get at someone's brain before there's been a change, maybe we need to do that earlier in women before some of this compensation starts to happen, which ultimately, can only work for so long.

How do we overcome the sex disparities seen in Alzheimer disease?

When we talk about disparities related to our sex and gender, the first thing to do with Alzheimer disease is just to educate the public. It's so important for researchers to get out there and translate their findings to bits that the public can take home with them. Because if folks don't know that they can change their behaviors in their 40s or 50s, that can have an impact on how well their brain is doing in their 70s and 80s. At that stage, they might not be so motivated to make those changes. This might be particularly important for women, as we're saying. Education is really the way to begin that process.

Are there any prevention methods geared towards tapping into specific regions of the brain?

That is an idea that's here. One example of that might not seem intuitive is exercise. I know that's not my topic in this poster, but throughout the conference, we’ve heard confirmation over and over again that exercise is a very strong preventative tool when it comes to brain health, dementia and Alzheimer's disease. We also know that exercise increases brain derived neurotrophic factor, and it does that preferentially in particular brain regions, one of which is the hippocampus. Even something that, which is maybe thought of as a general intervention abroad thing that you can do, can have very specific brain targets. This is the type of thing that's only going to be kind of more emphasized in the future as we talk about prevention, and what areas of the brain are we hoping to protect.

Transcript edited for clarity. Click here for more NeuroVoices.

1. Esposito R, Cieri F, Chiacchiaretta P, et al. Modifications in resting state functional anticorrelation between default mode network and dorsal attention network: comparison among young adults, health elders and mild cognitive impairment patients. Brain Imaging Behav. 2018;12(1):127-141. doi:10.1007/s11682-017-9686-y
2. Cieri F, Yang Z, Kinney J, Cummings JL, Cordes D, Caldwell JK. Interaction effect of sex and diagnosis on functional connectivity within the default network in healthy controls, mild cognitive impairment, and Alzheimer disease. Presented at: 2022 Alzheimer’s Association International Conference; July 31 to August 4; San Diego, CA. 68142
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