A multiancestry genetic score for Alzheimer’s disease could help identify people at risk years before symptoms emerge, according to researchers at Boston University.
Closing the Ancestry Gap in Genetic Risk Assessment
Most existing Alzheimer’s genetic studies have focused on people of European ancestry, limiting how well risk scores perform in other populations. The new polygenic risk score draws on genetic data from European, African American, Caribbean Hispanic, and East Asian populations to address that gap.
The development dataset included more than 63,000 people with Alzheimer’s and 484,000 controls. The score was then tested in an independent group of more than 27,000 people and validated in additional cohorts.
Performance improved notably among African American, Hispanic, and East Asian populations compared to earlier scores built primarily on European data. However, accuracy still varied across groups, highlighting the need for greater ancestral diversity in genetic research.
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For patients from underrepresented backgrounds, this disparity in risk prediction tools has real consequences. Without scores that perform equally well across populations, clinicians may miss warning signs in patients whose genetic profiles were not well-represented in the original studies. Widening the data sources to include more diverse participants is a step toward addressing that imbalance.
Measuring Risk Beyond APOE
The score was designed to measure genetic risk independently of APOE, whose ε4 variant is the strongest common genetic risk factor for late-onset Alzheimer’s. Researchers noted that combining APOE status with the broader polygenic risk score could eventually provide a more complete picture of inherited risk.
“These findings support integrating both APOE genotype and an APOE-excluded PRS for more precise risk stratification, enabling early identification even among APOE ε4 noncarriers,” the authors wrote.
The score also appeared to capture more than diagnosis likelihood. Higher scores correlated with poorer memory, executive function, and language performance, as well as smaller hippocampal volume on MRI and greater Alzheimer’s-related brain pathology. Associations between genetic risk and phosphorylated tau were stronger among women.
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In longitudinal analyses, people with very high genetic risk showed greater cognitive decline as they aged, particularly before diagnosis. That finding could prove valuable as the field moves toward identifying and treating the disease during its long presymptomatic stages.
Path Toward the Clinic
One promising direction involves combining genetic risk with emerging blood-based Alzheimer’s biomarkers, including phosphorylated tau. The researchers suggested that integrating the score with scalable blood tests could eventually help identify high-risk individuals before symptoms appear.
“Although modest in sample size, the convergence of genetic liability with this clinically validated biomarker shows the translational potential of integrating PRS with scalable blood-based assays to identify high-risk individuals even before symptoms emerge,” the researchers wrote.
The score is not yet ready for routine clinical use. Larger and more diverse datasets, standardized clinical thresholds, and integration into healthcare workflows will be needed before widespread adoption.
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