USC study finds key Alzheimer’s risk factor may behave differently in Hispanic older adults

Researchers at the USC Mark and Mary Stevens Neuroimaging and Informatics Institute (Stevens INI) at the Keck School of Medicine of USC analyzed brain imaging and clinical data from more than 17,000 participants across five major aging and Alzheimer’s disease studies. Their findings, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, showed that, while greater amyloid buildup was associated with cognitive impairment or carrying the APOE ε4 gene variant for both Hispanic and non-Hispanic white participants, Hispanic participants generally had lower amyloid levels than non-Hispanic white participants with the same characteristics.

Amyloid is a protein that can accumulate in the brain and form plaques, a hallmark biological sign of Alzheimer’s disease. APOE ε4 is the strongest common genetic risk factor for late-onset Alzheimer’s and has long been associated with a higher amyloid burden. The new findings suggest that this relationship may not be equally strong across populations.

“APOE ε4 is a major Alzheimer’s disease genetic risk factor, but our results suggest its relationship to amyloid buildup may be more nuanced in Hispanic populations,” said Cally Xiao, PhD, the study’s lead author and a researcher at the Stevens INI. “This work is important because it may influence how we interpret risk, understand cognitive decline, and ultimately design or apply treatments across diverse communities.”

Using GAAIN to unlock large-scale Alzheimer’s research

The study was made possible in part by the Global Alzheimer’s Association Interactive Network (GAAIN), a data-sharing platform developed at the Stevens INI with funding from the Alzheimer’s Association. GAAIN helps researchers discover, explore, and connect with large datasets from Alzheimer’s disease, related dementias, and aging studies around the world.

Using the GAAIN platform, the researchers identified studies that reported amyloid PET results using the Centiloid scale, a standardized method for comparing brain amyloid levels across different scanners, imaging tracers, and research centers. They then obtained data from five large sources: the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study, the Alzheimer’s Disease Neuroimaging Initiative, the Health and Aging Brain Study–Health Disparities, the Imaging Dementia–Evidence for Amyloid Scanning study, and the Standardized Centralized Alzheimer’s and Related Dementias Neuroimaging initiative.

By bringing these datasets together, the researchers were able to study patterns that would have been difficult to detect in any single cohort alone.

“This is exactly the kind of work GAAIN was built to enable,” said Arthur W. Toga, PhD, director of the Stevens INI and senior author of the study. “When researchers can identify compatible datasets, connect across studies, and conduct analyses at a scale that no one group could achieve independently, we gain a much clearer view of Alzheimer’s disease. That is especially important when we are trying to understand how disease biology may differ across populations that have historically been underrepresented in research.”

A closer look at amyloid burden across groups

The researchers examined data from 17,017 older adults, including 1,427 Hispanic participants. They used Centiloid values to compare brain amyloid burden while accounting for age, sex, education, and cognitive performance.

Across the combined sample, participants with mild cognitive impairment or dementia generally had higher amyloid levels than cognitively normal participants. APOE ε4 was also linked to higher amyloid levels in both Hispanic and non-Hispanic white groups. However, Hispanic participants had lower average amyloid burden than non-Hispanic whites across diagnosis groups. Among APOE ε4 carriers, Hispanic individuals with normal cognition or mild impairment also had lower amyloid levels than non-Hispanic whites.

While APOE ε4 was associated with amyloid pathology in both groups, the team found that the association was weaker among Hispanic participants. Non-Hispanic white participants with APOE ε4 were more than four times as likely to show evidence of amyloid pathology, whereas Hispanic participants with APOE ε4 were about two and a half times as likely.

“These findings do not mean that Hispanic adults are at lower risk for dementia,” Xiao said. “In fact, Hispanic populations face a higher overall burden of dementia. Instead, our results suggest that cognitive impairment in Hispanic older adults may not always be driven by amyloid in the same way, and that other biological, vascular, or social factors may also be important.”

Implications for Alzheimer’s research and treatment

The findings come at a critical moment for Alzheimer’s disease research, as anti-amyloid therapies are increasingly shaping the treatment landscape. Because these therapies are designed to target amyloid plaques in the brain, understanding how amyloid burden relates to cognition and genetic risk across different populations is essential.

The study’s authors caution that additional research is needed, including studies with larger samples of Hispanic participants, more detailed information on Hispanic origin and ancestry, and longitudinal data tracking amyloid changes and cognitive decline over time. They also note that vascular health and other medical conditions may contribute to some of the observed differences but do not fully explain them.

“Alzheimer’s disease is complex, and the path to cognitive decline may not look identical for every population,” Toga said. “To move toward more precise and equitable care, we need research that reflects that complexity. Large-scale data resources such as GAAIN are helping make that possible.”

About the study

In addition to Xiao and Toga, the study’s authors include Tyler Ard and Ioannis Pappas of the USC Stevens Neuroimaging and Informatics Institute; Ganna Blazhenets and Renaud La Joie of the University of California, San Francisco; the Alzheimer’s Disease Neuroimaging Initiative; and the Health and Aging Brain Study–Health Disparities Study Team.

Data used in the research were obtained through GAAIN, which is funded by the Alzheimer’s Association and powered by the Laboratory of Neuro Imaging at the USC Stevens Neuroimaging and Informatics Institute. The study was supported by the Global Alzheimer’s Association Interactive Network initiative of the Alzheimer’s Association, grant SG-20-678486-GAAIN2.