NeuroVoices: Jessica Caldwell, PhD, on the Association of Genetics and Alzheimer Disease

Jessica Caldwell, PhD

The Women’s Alzheimer’s Movement Prevention Center at Cleveland Clinic recently marked its first anniversary with a grant from the National Institutes of Health expected to total $1.8 million. The 4-year grant will be used to study the interactive effects of gender and sex on biological processes in Alzheimer disease (AD). Almost two-thirds of Americans living with AD are women, and of the more than 6 million people aged 65 and older with AD in the US, 3.8 million are women. For context, as a real a concern as breast cancer is to women’s health, women in their 60s are about as twice as likely to develop AD during the rest of their lives as they are to develop breast cancer.

Jessica Caldwell, PhD, director of the center and recipient of the grant, will utilize the grant to examine how gender-linked stress exposure and estrogen may interact to impact memory, inflammation in the body, and brain activation and connectivity in women at risk for AD. She hopes that the findings will help to inform development of interventions targeting stress and inflammation to reduce risk of the disease. Since 2016, the Women’s Alzheimer’s Movement has helped fund Caldwell’s sex-based research, providing the seed money to build the data infrastructure to apply for this grant, and eventually help establish the Women’s Alzheimer’s Movement Prevention Center.

Caldwell sat down with NeurologyLive on a new iteration of NeuroVoices to provide further detail on the specifics of the study, and the reasons for why expanding research on AD risk in women is critical to better understanding the disease. She also discussed the current knowledge of genetics and their association with AD, as well as their role in helping optimize clinical trials.

NeurologyLive: What is the plan going forward with this new grant from the NIH?

Jessica Caldwell, PhD: I received a 4-year grant from the NIH to study how gender and sex related factors might impact women’s risk for Alzheimer disease. I currently run a prevention clinic for Alzheimer disease for women. This grant will allow me to invite women back to the clinic and ask them about how many stressors they’ve been exposed to throughout their life and then also take some blood samples to measure their estrogen levels, because most of the women in my clinic are at midlife. We capture the whole range of the menopause transition. Our idea is that both stress and estrogen levels might interact to change the way that women’s brains work when they’re taking a memory test and might also change the level of inflammation that’s present in their blood. Both of those things we know are potentially ways that Alzheimer pathology can be facilitated if brain activity and inflammation and are abnormal in the long run.

What is currently known and unknown about the associations between genetics and Alzheimer disease?

There’s a huge amount that’s still left to be researched and that’s still unknown. What we do know in terms of this space is that women currently have twice the rates of Alzheimer disease as men do. Women also have a greater impact of certain genetic risk factors. In particular, the APOE4 allele presence impacts women’s risk of getting Alzheimer disease more than it does in men. It does that in a great way. Some studies have shown it to be as much as double the risk or even more for a woman versus a man having those alleles.

Beyond women vs men, we also know there’s a huge unknown amount in terms of racial and ethnic diversity. At this point, Black women have twice the rates of Alzheimer disease compared to non-Hispanic White women. Hispanic women have 1.5-times the rates of this. The research needs to focus on several different things, including whether or not we’re inviting people to research in the same way. A lot of studies have shown that white people are coming to the research because they’re recruited through the clinic, whereas non-White people get recruited because we’re supposed to recruit non-White people. It’s a very different way to sample people in terms of their concerns and risks. Some of the research that’s trying to get at race and ethnicity may show invalid results because of this. There are places that are doing excellent research that’s more balanced about race and ethnicity. Just a couple of places that come to mind are Columbia University, Massachusetts General Hospital, and the University of Michigan. All of these places are doing a great job at reversing that pattern we’ve seen in the literature.

Can you describe the complexities in compiling relatively homogenous populations for trials? What role does genetics play into this?

As just one example of a complexity, if we’re recruiting for studies within a clinic setting, we’re recruiting people who know about the clinic and are able to get the clinic. Just those 2 factors could eliminate people with lower education levels, who don’t have the same sort of new utilization or exposure to information. They might not know about the clinic. We are definitely excluding people who have lower socioeconomic status to where they might not have access to transportation to the clinic. These are things that we think about in the research design. It is a drawback. When we have a clinic where we’ve advertised nationally, it depends on the person’s view of the advertisements. It’s something to consider when we get that final research sample.

How can understanding genetics help us process drug development and make it more efficient?

I’m a neuropsychologist, so I’m not on the drug development side of clinical trials, but I would say that genetics, in addition to all these other factors we’ve talked about, will be important to consider. When we talk about genetics, why is the risk of Alzheimer disease different based on APOE? Why is it more impactful in women? Is it something that’s based on genetics, or is it a proxy for some sort of socioeconomic, sociocultural factor that is different between groups? I think that trying to personalize and capture the whole person when they come into clinical trials will be very important. That includes genetics, but not rely only on genetics as the mechanism of further tailoring development of drugs.

Transcript edited for clarity. For more iterations of NeuroVoices, click here.

REFERENCE

Women and Alzheimer’s. Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/what-is-alzheimers/women-and-alzheimer-s. Accessed September 21, 2021.