Min Young Chun, Sang-Hyuk Jung, Juran Choe, Seung-yeon Lee, Hang-Rai Kim, Hyo Jin Son, Yejoo Choi, Minyoung Cho, Beomsu Kim, Hyemin Jang, Seong Hye Choi, Jee Hyang Jeong, Sang Joon Son, Chang Hyung Hong, Hyun Woong Roh, Duk L. Na, Sang Won Seo, Hong-Hee Won, Jinsoo Seo, Hee Jin Kim
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We optimized PRS (optPRS) for AD, investigated its association with cognitive trajectories and AD phenotypes of cerebral organoids.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>Using genome-wide association study (GWAS) summary statistics from a European population, we developed optPRS to predict AD in Korean individuals (n = 1634). We analyzed the association between optPRS and cognitive trajectories (n = 771). We generated induced pluripotent stem cell–derived cerebral organoids from patients with high (n = 3) and low (n = 4) optPRS to evaluate amyloid beta (Aβ) and phosphorylated tau (p-tau) levels.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>OptPRS predicted AD dementia and Aβ positivity, independent of apolipoprotein E (<i>APOE</i>). Higher optPRSs correlated with rapid cognitive decline. Cerebral organoids from the high optPRS group exhibited increased Aβ insolubility and p-tau levels.</p>\n </section>\n \n <section>\n \n <h3> CONCLUSION</h3>\n \n <p>OptPRS predicted cognitive decline and AD phenotypes of cerebral organoids, supporting its use in risk assessments and drug-screening platform.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Optimized polygenic risk scores (optPRSs) improve the prediction of Alzheimer's disease (AD) dementia and amyloid beta positivity (Aβ+).</li>\n \n <li>High optPRS is associated with faster cognitive decline, particularly in Aβ+.</li>\n \n <li>Induced pluripotent stem cell (iPSC)–derived cerebral organoids from high optPRSs show high Aβ insolubility and phosphorylated tau (p-tau).</li>\n \n <li>PRS genetic risk stratification provides insight into AD progression and pathology.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 9","pages":""},"PeriodicalIF":11.1000,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12441735/pdf/","citationCount":"0","resultStr":"{\"title\":\"Polygenic risk score of Alzheimer's disease is associated with cognitive trajectories and phenotypes of cerebral organoids\",\"authors\":\"Min Young Chun, Sang-Hyuk Jung, Juran Choe, Seung-yeon Lee, Hang-Rai Kim, Hyo Jin Son, Yejoo Choi, Minyoung Cho, Beomsu Kim, Hyemin Jang, Seong Hye Choi, Jee Hyang Jeong, Sang Joon Son, Chang Hyung Hong, Hyun Woong Roh, Duk L. 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Polygenic risk score of Alzheimer's disease is associated with cognitive trajectories and phenotypes of cerebral organoids
INTRODUCTION
Polygenic risk score (PRS) identifies individuals at high genetic risk for Alzheimer's disease (AD), but its utility in predicting cognitive trajectories and AD pathologies remains unclear. We optimized PRS (optPRS) for AD, investigated its association with cognitive trajectories and AD phenotypes of cerebral organoids.
METHODS
Using genome-wide association study (GWAS) summary statistics from a European population, we developed optPRS to predict AD in Korean individuals (n = 1634). We analyzed the association between optPRS and cognitive trajectories (n = 771). We generated induced pluripotent stem cell–derived cerebral organoids from patients with high (n = 3) and low (n = 4) optPRS to evaluate amyloid beta (Aβ) and phosphorylated tau (p-tau) levels.
RESULTS
OptPRS predicted AD dementia and Aβ positivity, independent of apolipoprotein E (APOE). Higher optPRSs correlated with rapid cognitive decline. Cerebral organoids from the high optPRS group exhibited increased Aβ insolubility and p-tau levels.
CONCLUSION
OptPRS predicted cognitive decline and AD phenotypes of cerebral organoids, supporting its use in risk assessments and drug-screening platform.
Highlights
Optimized polygenic risk scores (optPRSs) improve the prediction of Alzheimer's disease (AD) dementia and amyloid beta positivity (Aβ+).
High optPRS is associated with faster cognitive decline, particularly in Aβ+.
Induced pluripotent stem cell (iPSC)–derived cerebral organoids from high optPRSs show high Aβ insolubility and phosphorylated tau (p-tau).
PRS genetic risk stratification provides insight into AD progression and pathology.
期刊介绍：
Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.
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