DREAM Scholar Explores Gene and Environment Interactions Underlying Alzheimer’s Disease

LEXINGTON, Ky. (Aug. 7, 2024) – Despite the prevalence and toll of late-onset Alzheimer’s disease—the most common type, which begins after age 65— causes of the disease remain only partly understood.  Is it genes? Lifestyle? Environment?

Current scientific understanding says it’s a combination of these factors, but we still don’t understand exactly how they interact to affect someone’s risk of developing the disease.

Research indicates that more than 80 genetic variants might have a role in someone’s susceptibility to late onset-Alzheimer’s disease (LOAD), and twin studies suggest that between 60-80% of cases are heritable. But not everyone who has LOAD risk genes develops the condition, and some people without risk genes do.  Further complicating matters is that risk genes seem to have different effects across racial and ethnic groups, and environmental exposures can amplify or lessen the role of risk genes.

Xian Wu, PhD, has ambitious goals to elucidate how genetic and environmental factors interact to cause late-onset Alzheimer’s disease. A post-doctoral fellow in the UK College of Public Health Department of Biostatistics and the Sanders-Brown Center on Aging, as well as a DREAM (Disparities Researchers Equalizing Access for Minorities) Scholar with the UK Center for Clinical and Translational Science, she has received a prestigious New Investigator Award (NIA) from National Alzheimer’s Coordinating Center (NACC) to support her research.

Wu is particularly interested in examining genetic and environmental risk factors across the lifespan in diverse and underrepresented populations, which experience greater prevalence of the disease but are less likely to receive a timely diagnosis or be included in research.

“Based on national reporting, older Black Americans are approximately twice as likely to develop Alzheimer’s disease or dementia, and older Hispanic/Latino Americans have one and a half times greater risk, but they are less likely to be diagnosed through routine care. I want to address these health equity issues,” Wu says.

She explains that most previous research on causes of LOAD has looked at one-to-one interactions between a single gene and a single environmental exposure—but she wants to get beyond this.

“For this study, I will construct two comprehensive risk scores—a polygenetic risk score and an environmental risk score. I’ll construct midlife scores (for the 45-65 age period) and late life scores (beyond 65 years old) to see how the midlife and later life environmental risk scores modify the effects of the polygenetic risk scores in Alzheimer’s disease. Heritability for LOAD is not constant. Gene-environment interactions may vary during midlife and later life, so it’s necessary to examine these interactions using a life-course perspective.”

One challenge, Wu says, is constructing polygenetic risk scores for non-white populations.

“This is a difficult topic in Alzheimer’s disease research because most participants in genetic studies of the disease have been non-Hispanic white individuals with European ancestry.”

To develop the polygenetic risk scores, Wu will utilize the Alzheimer's Disease Genetics Consortium (ADGC) genetic data and published genome-wide association studies (GWAS) summary statistics. Midlife and later-life environmental risk scores will be constructed by ethnicity/race based on various environmental indicators in the NACC data, including social, physical, behavioral, and lifestyle variables.

She will then test how the effects of polygenetic risk scores are modified by midlife and later-life environmental risk scores, particularly across racial/ethnic groups. No previous research has utilized comprehensive scores to examine gene and environment interactions on vulnerability and resilience to LOAD by ethnicity/race during midlife and later life.

Wu says that the University of Kentucky is an ideal environment to conduct this type of research. She points to the Sanders-Brown Center on Aging, one of the first ten Alzheimer’s Disease Centers ever funded by the National Institutes of Health, which has provided her with mentorship and a letter of support for her NIA application.

The DREAM Scholars Program, which provides training and career development to health equity researchers, has also been instrumental to Wu’s success.

“I’m new to the field of Alzheimer’s research, and there’s a learning curve. But I feel really encouraged and it’s a great opportunity to learn from DREAM scholars in other fields.”

She says the DREAM seminar series has also helped her refine her research and grant writing skills.

Her mentor in the program is Yuriko Katsumata, PhD, an associate professor of bbiostatistics with the Sanders-Brown Center on Aging.  Wu also works in the lab of David Fardo, PhD, professor in the UK College of Public Health and an expert in researching genetic risk factors for dementia.

“I learn a lot from working in his lab. We have lab meetings every week, which a very nice discussion environment where we can present work in progress and get feedback. It feels more like a family,” she says.

Additional mentors include Erin Abner, PhD, professor in the UK College of Public Health Department of Epidemiology with joint appointments in the UK Sanders-Brown Center on Aging and the Department of Biostatistics; and Pete Nelson, MD, PhD, director of the Neuropathology Lab and professor in the UK College of Medicine with an appointment in Sanders-Brown Center on Aging; and Bryan James, PhD, epidemiologist with the Rush University Alzheimer’s Disease Center.

“All of my mentors are outstanding. I’m very grateful for them, for the lab, and for all the support I get from my department, college, and the DREAM program. I look forward to results of this research so that I can apply to other grants in the future.”

The University of Kentucky Center for Clinical and Translational Science is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001998. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Media Contact: Mallory Profeta, mallory.profeta@uky.edu