Chun Min Young, Jung Sang-Hyuk, Choe Juran, Lee Seung-Yeon, Kim Hang-Rai, Son Hyo Jin, Choi Yejoo, Cho Minyoung, Kim Beomsu, Jang Hyemin, Choi Seong Hye, Jeong Jee Hyang, Son Sang Joon, Hong Chang Hyung, Roh Hyun Woong, Na Duk L, Seo Sang Won, Won Hong-Hee, Seo Jinsoo, Kim Hee Jin
Departments of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea.
Alzheimers Dement. 2025 Sep;21(9):e70660. doi: 10.1002/alz.70660.
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.
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.
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.
OptPRS predicted cognitive decline and AD phenotypes of cerebral organoids, supporting its use in risk assessments and drug-screening platform.
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.
多基因风险评分（PRS）可识别出患阿尔茨海默病（AD）遗传风险高的个体，但其在预测认知轨迹和AD病理方面的效用仍不明确。我们优化了AD的PRS（optPRS），研究了其与脑类器官的认知轨迹和AD表型的关联。
利用来自欧洲人群的全基因组关联研究（GWAS）汇总统计数据，我们开发了optPRS来预测韩国个体（n = 1634）的AD。我们分析了optPRS与认知轨迹（n = 771）之间的关联。我们从高（n = 3）和低（n = 4）optPRS的患者中生成诱导多能干细胞衍生的脑类器官，以评估淀粉样β蛋白（Aβ）和磷酸化tau蛋白（p-tau）水平。
OptPRS可预测AD痴呆和Aβ阳性，与载脂蛋白E（APOE）无关。较高的optPRS与快速认知衰退相关。高optPRS组的脑类器官表现出Aβ不溶性增加和p-tau水平升高。
OptPRS可预测脑类器官的认知衰退和AD表型，支持其在风险评估和药物筛选平台中的应用。
优化的多基因风险评分（optPRS）改善了对阿尔茨海默病（AD）痴呆和淀粉样β蛋白阳性（Aβ+）的预测。高optPRS与更快的认知衰退相关，尤其是在Aβ+中。来自高optPRS的诱导多能干细胞（iPSC）衍生的脑类器官显示出高Aβ不溶性和磷酸化tau蛋白（p-tau）。PRS遗传风险分层为AD进展和病理提供了见解。
