medRxiv : the preprint server for health sciences · 2026
Alzheimer's Polygenic Risk Scores Are Not Interchangeable: Evidence from 1,752 Models.
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Ward Elizabeth L, Nelson Peter T, Katsumata Yuriko, Fardo David W, Jicha Gregory A, Alzheimer’s Disease Neuroimaging Initiative, Miller Justin B
Аннотация
INTRODUCTION: Polygenic risk scores (PRS) may improve Alzheimer's disease (AD) risk prediction before symptom onset, yet choosing an appropriate model can be challenging.
METHODS: Using the standardized GenoPred pipeline, 1,752 PRS models (9 algorithms; 584 configurations; 3 genome-wide association studies) were evaluated and stratified by genetic ancestry and APOE diplotype. PRS models were evaluated using 11,200 clinical or autopsy-confirmed AD cases and 19,321 controls age ≥65 from the Alzheimer's Disease Sequencing Project Release 5.
RESULTS: PRS results were not consistent across methodologies (Spearman's ρ: -0.49 to 1), with >95% of individuals having PRS in both the top and bottom risk deciles. Top-performing PRS were effective at stratifying AD risk across ancestries (AFR: P =2.04×10 - 26 ; AMR: P =4.57×10 -21 ; EAS: P =6.21×10 -40 ; EUR: P =7.90×10 -187 ).
DISCUSSION: PRS parameters should be optimized for each ancestry. Contradictory signals across methodologies underscore the need for carefully choosing suitable PRS methods and fine-tuning algorithmic parameters to ensure accuracy and consistency.
DATA AVAILABILITY: Access to the ADSP is controlled by The National Institute on Aging Genetics of Alzheimer's Disease (NIAGADS). All scripts used to analyze the data are freely available at https://github.com/jmillerlab/prs_comparisons .
METHODS: Using the standardized GenoPred pipeline, 1,752 PRS models (9 algorithms; 584 configurations; 3 genome-wide association studies) were evaluated and stratified by genetic ancestry and APOE diplotype. PRS models were evaluated using 11,200 clinical or autopsy-confirmed AD cases and 19,321 controls age ≥65 from the Alzheimer's Disease Sequencing Project Release 5.
RESULTS: PRS results were not consistent across methodologies (Spearman's ρ: -0.49 to 1), with >95% of individuals having PRS in both the top and bottom risk deciles. Top-performing PRS were effective at stratifying AD risk across ancestries (AFR: P =2.04×10 - 26 ; AMR: P =4.57×10 -21 ; EAS: P =6.21×10 -40 ; EUR: P =7.90×10 -187 ).
DISCUSSION: PRS parameters should be optimized for each ancestry. Contradictory signals across methodologies underscore the need for carefully choosing suitable PRS methods and fine-tuning algorithmic parameters to ensure accuracy and consistency.
DATA AVAILABILITY: Access to the ADSP is controlled by The National Institute on Aging Genetics of Alzheimer's Disease (NIAGADS). All scripts used to analyze the data are freely available at https://github.com/jmillerlab/prs_comparisons .