Evaluating polygenic risk score prediction performance for Alzheimer's disease in a population-based Hispanic cohort using single- and multi-ancestry modelsResearch in context
Summary: Background: The Polygenic risk score (PRS) is effective in predicting Alzheimer's Disease (AD) risk among Europeans but remains understudied in Hispanics. Genome-wide association studies (GWAS) based on multiple ancestries can improve PRS prediction. We used GWAS data from the largest...
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Elsevier
2025-09-01
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| Series: | The Lancet Regional Health. Americas |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667193X2500208X |
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| author | Yuexuan Xu Min Qiao Tamil I. Gunasekaran Yian Gu Dolly Reyes-Dumeyer Angel Piriz Danurys Sanchez Belisa Soriano Yahaira Franco Zoraida Dominguez Coronado Patricia Recio Diones Rivera Mejia Martin Medrano Rafael A. Lantigua Lawrence Honig Jennifer J. Manly Adam M. Brickman Badri N. Vardarajan Richard Mayeux |
| author_facet | Yuexuan Xu Min Qiao Tamil I. Gunasekaran Yian Gu Dolly Reyes-Dumeyer Angel Piriz Danurys Sanchez Belisa Soriano Yahaira Franco Zoraida Dominguez Coronado Patricia Recio Diones Rivera Mejia Martin Medrano Rafael A. Lantigua Lawrence Honig Jennifer J. Manly Adam M. Brickman Badri N. Vardarajan Richard Mayeux |
| author_sort | Yuexuan Xu |
| collection | DOAJ |
| description | Summary: Background: The Polygenic risk score (PRS) is effective in predicting Alzheimer's Disease (AD) risk among Europeans but remains understudied in Hispanics. Genome-wide association studies (GWAS) based on multiple ancestries can improve PRS prediction. We used GWAS data from the largest available African, European, and Hispanic populations and performed PRS analyses using novel methodologies to evaluate the performance of single- and multi-ancestry PRS models in predicting AD risk among Hispanic population. Methods: Prediction performance of Apolipoprotein-E (APOE), single-ancestry PRS, and multi-ancestry PRS derived from GWAS-focused and method-focused approaches to clinical AD, incident AD, and cognition and were evaluated in 2961 Hispanic people from two large studies. The GWAS-focused approach constructs PRS based on multi-ancestry GWAS, while the method-focused approach uses novel multi-ancestry PRS methods, integrating GWAS summary statistics across ancestries. Ten repetitions of 5-fold cross-validation were used. In a subset, plasma biomarker data were used in a tuning-validation split to examine PRS performance in predicting single and combined biomarkers. Findings: The multi-ancestry PRS excluding APOE, constructed using the method-focused approach, outperformed both single-ancestry and multi-ancestry PRSs from the GWAS-focused approach. The best method-focused PRS, incorporating summary statistics from GWASs of African, European, and Hispanic populations, explained up to 1.6%, 3.9%, and 1.7% of the variance in clinical AD, incident AD, and cognition, respectively–comparable to, or even higher than, the variance explained by the APOE. Similar findings were observed in biomarker analyses. APOE accounted for more variation in plasma P-tau levels and PRS explained more variation in Aβ levels. Interpretation: Integrating novel multi-ancestry PRS methods (e.g., PROSPER/PRS-CSx) with GWAS across ancestries enhances prediction accuracy for AD risk among Hispanic population. APOE and PRS may point to different biological aspects of AD. Funding: National Institutes of Health R01 AG072474, RF1 AG066107, 5R37AG015473, RF1AG015473, R56AG051876, R01 AG067501, and UL1TR001873. |
| format | Article |
| id | doaj-art-1799524b23ab44ea9934e218f291e984 |
| institution | DOAJ |
| issn | 2667-193X |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | The Lancet Regional Health. Americas |
| spelling | doaj-art-1799524b23ab44ea9934e218f291e9842025-08-20T03:13:59ZengElsevierThe Lancet Regional Health. Americas2667-193X2025-09-014910119810.1016/j.lana.2025.101198Evaluating polygenic risk score prediction performance for Alzheimer's disease in a population-based Hispanic cohort using single- and multi-ancestry modelsResearch in contextYuexuan Xu0Min Qiao1Tamil I. Gunasekaran2Yian Gu3Dolly Reyes-Dumeyer4Angel Piriz5Danurys Sanchez6Belisa Soriano7Yahaira Franco8Zoraida Dominguez Coronado9Patricia Recio10Diones Rivera Mejia11Martin Medrano12Rafael A. Lantigua13Lawrence Honig14Jennifer J. Manly15Adam M. Brickman16Badri N. Vardarajan17Richard Mayeux18Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USATaub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USATaub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USATaub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, and the New York Presbyterian Hospital, New York, NY, USATaub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USATaub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USATaub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USAUniversidad Nacional Pedro Henríquez Urena, Santo Domingo, Dominican RepublicClinica Corominas, Santiago, Dominican RepublicClínica Gregorio Hernandez, Puerto Plata, Dominican RepublicCEDIMAT, Santo Domingo, Dominican RepublicCEDIMAT, Santo Domingo, Dominican Republic; Universidad Nacional Pedro Henríquez Urena, Santo Domingo, Dominican RepublicPontificia Universidad Catolica Madre y Maestra (PUCMM), Santiago, Dominican RepublicTaub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, and the New York Presbyterian Hospital, New York, NY, USATaub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, and the New York Presbyterian Hospital, New York, NY, USATaub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, and the New York Presbyterian Hospital, New York, NY, USATaub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, and the New York Presbyterian Hospital, New York, NY, USATaub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USATaub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, and the New York Presbyterian Hospital, New York, NY, USA; Corresponding author. Gertrude H. Sergievsky, Department of Neurology, NewYork-Presbyterian/Columbia University Irving Medical Center, USA.Summary: Background: The Polygenic risk score (PRS) is effective in predicting Alzheimer's Disease (AD) risk among Europeans but remains understudied in Hispanics. Genome-wide association studies (GWAS) based on multiple ancestries can improve PRS prediction. We used GWAS data from the largest available African, European, and Hispanic populations and performed PRS analyses using novel methodologies to evaluate the performance of single- and multi-ancestry PRS models in predicting AD risk among Hispanic population. Methods: Prediction performance of Apolipoprotein-E (APOE), single-ancestry PRS, and multi-ancestry PRS derived from GWAS-focused and method-focused approaches to clinical AD, incident AD, and cognition and were evaluated in 2961 Hispanic people from two large studies. The GWAS-focused approach constructs PRS based on multi-ancestry GWAS, while the method-focused approach uses novel multi-ancestry PRS methods, integrating GWAS summary statistics across ancestries. Ten repetitions of 5-fold cross-validation were used. In a subset, plasma biomarker data were used in a tuning-validation split to examine PRS performance in predicting single and combined biomarkers. Findings: The multi-ancestry PRS excluding APOE, constructed using the method-focused approach, outperformed both single-ancestry and multi-ancestry PRSs from the GWAS-focused approach. The best method-focused PRS, incorporating summary statistics from GWASs of African, European, and Hispanic populations, explained up to 1.6%, 3.9%, and 1.7% of the variance in clinical AD, incident AD, and cognition, respectively–comparable to, or even higher than, the variance explained by the APOE. Similar findings were observed in biomarker analyses. APOE accounted for more variation in plasma P-tau levels and PRS explained more variation in Aβ levels. Interpretation: Integrating novel multi-ancestry PRS methods (e.g., PROSPER/PRS-CSx) with GWAS across ancestries enhances prediction accuracy for AD risk among Hispanic population. APOE and PRS may point to different biological aspects of AD. Funding: National Institutes of Health R01 AG072474, RF1 AG066107, 5R37AG015473, RF1AG015473, R56AG051876, R01 AG067501, and UL1TR001873.http://www.sciencedirect.com/science/article/pii/S2667193X2500208XPolygenic risk scoreCaribbean HispanicsPredictionAlzheimer'sBiomarker |
| spellingShingle | Yuexuan Xu Min Qiao Tamil I. Gunasekaran Yian Gu Dolly Reyes-Dumeyer Angel Piriz Danurys Sanchez Belisa Soriano Yahaira Franco Zoraida Dominguez Coronado Patricia Recio Diones Rivera Mejia Martin Medrano Rafael A. Lantigua Lawrence Honig Jennifer J. Manly Adam M. Brickman Badri N. Vardarajan Richard Mayeux Evaluating polygenic risk score prediction performance for Alzheimer's disease in a population-based Hispanic cohort using single- and multi-ancestry modelsResearch in context The Lancet Regional Health. Americas Polygenic risk score Caribbean Hispanics Prediction Alzheimer's Biomarker |
| title | Evaluating polygenic risk score prediction performance for Alzheimer's disease in a population-based Hispanic cohort using single- and multi-ancestry modelsResearch in context |
| title_full | Evaluating polygenic risk score prediction performance for Alzheimer's disease in a population-based Hispanic cohort using single- and multi-ancestry modelsResearch in context |
| title_fullStr | Evaluating polygenic risk score prediction performance for Alzheimer's disease in a population-based Hispanic cohort using single- and multi-ancestry modelsResearch in context |
| title_full_unstemmed | Evaluating polygenic risk score prediction performance for Alzheimer's disease in a population-based Hispanic cohort using single- and multi-ancestry modelsResearch in context |
| title_short | Evaluating polygenic risk score prediction performance for Alzheimer's disease in a population-based Hispanic cohort using single- and multi-ancestry modelsResearch in context |
| title_sort | evaluating polygenic risk score prediction performance for alzheimer s disease in a population based hispanic cohort using single and multi ancestry modelsresearch in context |
| topic | Polygenic risk score Caribbean Hispanics Prediction Alzheimer's Biomarker |
| url | http://www.sciencedirect.com/science/article/pii/S2667193X2500208X |
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