Non‐ Polygenic risk score derived from European ancestry data are more predictive of dementia among Hispanics who are ε4 carriers.

Background: Despite concerns about the transferability of polygenic risk scores (PRS) derived from European ancestry data to Hispanics, recent research suggests that many genetic loci identified through European ancestry genome‐wide association studies (GWAS) for complex traits are also relevant in Hispanics. Furthermore, studies on dementia have shown improved PRS performance in this group, even with PRS developed from European GWAS. Recent research also indicates that ε4‐independent PRS associations vary depending on ε4 status. This study evaluates the relationship between multiple recent European GWAS‐derived ‐independent PRS in Hispanics and the interaction between ε4 and PRS in relation to Alzheimer’s Disease (AD).

Methods: We constructed a range of PRS based on three recently published GWAS (Kunkle et al., 2019, Bellenguez et al., 2022, FinnGen) of European ancestry among 1,429 Hispanics from the Washington Heights‐Hamilton Heights‐Inwood Community Aging Project (WHICAP) using clumping and thresholding methods. For each GWAS, we first evaluated the associations of several ‐value thresholds with AD to determine the threshold for further analysis. Empirical ‐values were used to avoid overfitting for the optimized PRS. We then tested whether and how ε4 can modify the association between PRS and AD. All associations were fitted by logistic regression with sex, age, education, and the first 5 principal components as covariates.

Results: Across all European GWAS, the optimal ‐threshold for the most predictive PRS is at a conservative ‐threshold (Kunkle: 2.87e‐6, Bellenguez: 1.11e‐6, FinnGen: 1.80e‐5). PRS constructed based on the Bellenguez GWAS are most strongly associated with AD (OR = 1.29, 95% CI: 1.17‐1.42), and the FinnGen‐derived PRS show the least association (OR = 1.06, 95% CI: 0.98‐1.14). The association of all three PRSs is stronger among ε4 carriers (OR: 1.51, 95% CI: 1.26‐1.81; OR: 1.60, 95% CI: 1.35‐1.91; OR: 1.12, 95% CI: 0.97‐1.26) compared to non‐carriers (OR: 1.09, 95% CI: 0.96‐1.23; OR: 1.16, 95% CI: 1.03‐1.31; OR: 1.03, 95% CI: 0.93‐1.14). Similar findings were observed concerning cognition and progression to dementia.

Conclusion: PRS derived from a European GWAS identified individuals at high risk for AD dementia among Hispanics, and the association is strongest among ε4 carriers.