Multi-ancestry genetic score improves risk prediction for Alzheimer's disease

Late-onset Alzheimer disease (AD) is a progressive disorder characterized by cognitive decline and memory impairment, affecting an estimated 6.9 million people in the U.S. The clinical course of AD unfolds over many years, often beginning with subtle cognitive changes before progressing to overt dementia. Although the rate of decline varies across individuals, growing evidence suggests that genetic factors play a central role in shaping both the onset and trajectory of cognitive deterioration.

While the APOE ε4 allele remains the strongest known genetic risk factor, genome-wide association studies (GWAS) have identified numerous additional common and rare variants contributing to susceptibility primarily in individuals of European ancestry (EA) and to a lesser extent in other populations. Polygenic risk score (PRS) is a numerical estimate of an individual's genetic susceptibility to a specific disease. However, previously derived PRS for AD perform inconsistently across diverse ancestries.

In a new study, researchers describe the development and validation of a multi-ancestry PRS for AD that performs much better than previously constructed ones, especially for genetically diverse groups. This expanded representation of population groups is crucial for developing more robust and universally applicable PRS models, which can improve risk prediction among an ancestrally diverse group of patients.

A critical challenge in the application of PRS lies in the underrepresentation of diverse genetic ancestries in AD GWAS datasets, which include predominantly white individuals of European ancestry. The availability of GWAS data from diverse populations, including African American, Hispanic and East Asian, provides an opportunity to enhance the transferability and accuracy of PRS across multiple ancestries."