Cally Xiao was sifting through brain scans of more than 17,000 older adults when she noticed a subtle but significant pattern: Hispanic participants, even those carrying the APOE ε4 gene—the strongest known genetic risk factor for Alzheimer’s—showed lower levels of amyloid buildup than their non-Hispanic white counterparts. At the USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Xiao and her team uncovered findings that challenge long-held assumptions about how Alzheimer’s risk unfolds across populations. Their study, published in Alzheimer's & Dementia, analyzed data from five major aging and Alzheimer’s research initiatives, revealing that while amyloid accumulation is still linked to cognitive decline and APOE ε4 in both groups, the strength of that link appears to differ. For Hispanic adults, the presence of the high-risk gene does not translate to the same degree of amyloid burden—a discovery that could reshape how we assess risk and design treatments in diverse communities.
This research matters because Alzheimer’s diagnostics and drug development have largely been based on studies dominated by non-Hispanic white participants. When biology may play out differently in underrepresented groups, one-size-fits-all approaches can miss the mark. The team used the Centiloid scale—a standardized method for measuring amyloid levels across different imaging technologies—to harmonize data from varied sources, including the Alzheimer’s Disease Neuroimaging Initiative and the Health and Aging Brain Study–Health Disparities. By pooling data through the Global Alzheimer's Association Interactive Network (GAAIN), developed at the Stevens INI, they achieved a scale of analysis impossible within a single study.
Among the 17,017 participants, 1,427 identified as Hispanic. After adjusting for age, sex, education, and cognitive performance, the researchers found that Hispanic individuals consistently showed lower amyloid levels. Even among APOE ε4 carriers—those expected to have the highest risk—Hispanic participants with normal cognition or mild impairment had measurably less amyloid accumulation than non-Hispanic whites. The association between APOE ε4 and amyloid pathology, while present, was notably weaker in the Hispanic group. This suggests that genetic risk may not operate uniformly across ethnicities, and that other biological, environmental, or social factors could be at play.
The implications are profound. If APOE ε4 confers less amyloid burden in Hispanic populations, current risk prediction models may overestimate danger for these individuals. Conversely, cognitive decline in the presence of lower amyloid might point to other underlying causes of dementia that are not yet well understood. "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 Xiao. As Alzheimer’s research moves toward precision medicine, studies like this underscore the need to include diverse populations not just for equity, but for scientific accuracy. With tools like GAAIN enabling large-scale collaboration, the path forward is clearer: to understand Alzheimer’s in all its forms, science must reflect the full diversity of those it aims to serve.