Brain Research Finds Notable Differences in Changes Based on Sex and Race

Two new Cleveland Clinic studies that delve into Alzheimer’s disease-related brain changes highlight the need for a fuller understanding of how race and sex influence the condition.

The research was led by Jessica Caldwell, PhD, E.L. Wiegand Chair and Director for Women's Alzheimer's Movement Prevention and Research Center at the Cleveland Clinic Lou Ruvo Center for Brain Health.

At the 2024 Alzheimer's Association International Conference in June, Dr. Caldwell presented the research:

• Impacts of sex and ethnic background on the relationship between stress and hippocampal volumes.
• Differential effects of sex on hippocampal volume and cortical thickness in a racially and ethnically diverse cohort across the Alzheimer’s disease continuum.

Stress and hippocampal volumes

An overwhelming majority of research on sex differences in Alzheimer’s to date has been done on non-Hispanic white populations. Dr. Caldwell aims to broaden scientific understanding.

“Women, and particularly African American and Hispanic and Latino women, are at higher risk for Alzheimer’s disease than men,” says Dr. Caldwell. “Without broadening our research, we miss opportunities to understand Alzheimer’s disease, as well as opportunities for developing new assessment and treatment approaches for all people.”

Using data from the Health & Aging Brain Study — Health Disparities, the stress study reviewed data from a cohort of Hispanic/Latino, African American, and non-Hispanic white individuals to see whether the relationship between stress and hippocampal volumes would differ in men versus women.

Research fellow Katie Stypulkowski, PhD, explains that, “Chronic stress is a risk for Alzheimer's and can have impacts on hippocampal volumes, and stress can differ by race, ethnicity and sex. We also know hippocampal volumes can differ by race and ethnicity. So we wanted to look at that relationship in a multi-ethnic cohort and see how these things are behaving when we look across race and ethnicity as well also across sex.”

The cohort of older adults included 482 African Americans, 817 non-Hispanic whites, and 727 Hispanic/Latino individuals. The Chronic Stress Scale total score was the independent variable.

Among Hispanic/Latino individuals, the researchers found significant interaction between chronic stress and sex on right (t(711)=2.53, P =.01) and left hippocampal volumes (t(719)= 2.57, P =.01). The men showed lower hippocampal volumes as chronic stress increased, while Hispanic/Latino women did not.

In the non-Hispanic white and African American groups, sex did not moderate the relationship between stress and hippocampal volumes.

“What we're gathering is that at an older age, Hispanic and Latino men may be particularly vulnerable to chronic stress in a way that for some reason Hispanic and Latino women are not,” says Dr. Stypulkowski.

The differences in hippocampal sizes were not dramatic, but they were notable.

“The Chronic Stress Scale goes up to about 40,” says Dr. Stypulkowski. “At the high end of chronic stress for these Hispanic and Latino men, we're seeing hippocampal volumes decrease by up to 0.4 cubic millimeters. It isn't a huge change, but it is statistically significant. And this is all corrected for whole brain volume. So something unique is going on in the hippocampus of Hispanic men with increased chronic stress.”

The results raise new questions, and Dr. Stypulkowski says potential areas of further research include the role of inflammation and other conditions.

“Inflammation is a risk factor for Alzheimer's disease, and inflammation and stress are closely tied,” she says. “So that's something we're considering looking at as well as variations in the appraisal of stress, social support, other medical conditions and mental health conditions. There's a lot that we can do in trying to better understand what is going on in this unique relationship.”

Hippocampal volume and cortical thickness along the Alzheimer’s continuum

Homogeneity of research samples also has limited the generalizability of studies showing sex differences in structural resilience in the context of Alzheimer’s disease. Previous studies from mainly white cohorts suggest a female-specific, time-limited resilience in cortical thickness and possibly hippocampal volume in the presence of amyloid.

The purpose of this study was to incorporate ethnic diversity. Researchers examined (also using data from the Health & Aging Brain Study — Health Disparities) 798 non-Hispanic white, 470 African American, and 713 Hispanic/Latino participants with Alzheimer’s disease pathology. They looked for sex differences in structural brain resilience expressed as stable hippocampal volume and cortical thickness (including superior and middle temporal, isthmus and posterior cingulate, precuneus and inferior parietal).

Their hypothesis was that women with Alzheimer’s would show structural resilience when cognitively normal but not when mildly cognitively impaired, and that men with Alzheimer’s would show atrophy regardless of cognitive function.

Results showed that cognitively normal non-Hispanic white women and African American men demonstrated hippocampal resilience in the presence of amyloid plaque but showed atrophy when mildly cognitively impaired.

Similarly, cognitively normal African American women and Hispanic/Latino men retained cortical thickness. 

Researcher Taylor Levine, PhD, says the group expected to see brain resilience among the cognitively normal women across the racial groups, and atrophy among the men regardless of disease stage. The race-dependent differences were unexpected.

“In the non-Hispanic white female cohort, we did replicate previous findings of hippocampal volume reserve that we've seen in these other samples,” says Dr. Levine. “But when we looked at hippocampal volume in the African American sample, we saw the opposite effect, where men had reserve but women didn't. So the sex effect was completely opposite of what we expected.”

Dr. Levine says she even checked to ensure she hadn’t made a coding error (she hadn’t).

“I think that the results highlight, again, that we don't exist in a vacuum, and that there are a lot of other things that might be affecting our brain volume, not just how much pathology you have,” she says.

While the results point to more questions, and the researchers were not able to robustly replicate prior findings done in non-Hispanic white groups. “That’s important for informing our future work of trying to understand health and social factors that impact cognitive aging,” she says. “This highlights the work that needs to be done to provide the best care for the broad population that comes into our clinics.”