Cell‐based polygenic risk scores predict clinical progression and prioritize network‐based therapeutic targets in Alzheimer's disease

IF 12.8 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2026-10-06 DOI:10.1002/alz.71895

Nathan Sahelijo, Priya Rajagopalan, Lu Qian, Rufuto Rahman, Daniel Goldstein, Sophia I. Thomopoulos, David A. Bennett, Lindsay A. Farrer, Thor D. Stein, Li Shen, Heng Huang, Kwangsik Nho, Andrew J. Saykin, Christos Davatzikos, Paul M. Thompson, Julia TCW, Gyungah R. Jun

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引用次数: 0

Abstract

BACKGROUND Late‐onset Alzheimer's disease (AD) exhibits substantial biological heterogeneity. We developed a framework linking cell‐type–specific polygenic risk profiles to precision medicine in AD. METHODS Cell‐based polygenic risk scores (cbPRSs) derived from single‐nucleus RNA‐seq co‐expression networks were evaluated in Alzheimer's Disease Neuroimaging Initiative (ADNI) and Framingham Heart Study (FHS) cohorts. Network hubs were prioritized using a graph‐based PageRank algorithm and candidate drugs were validated in human‐induced pluripotent stem cell (hiPSC)–derived astrocytes. RESULTS Cell‐based PRS analysis identified two genetic risk axes independent of network cell‐type labels: an apolipoprotein E ( APOE )–concentrated axis (Ast‐M2/Oli‐M45) and an APOE ‐independent axis (Ast‐M10/Oli‐M50), which predicted accelerated progression to AD (hazard ratio: 1.25–2.02) and correlated with localized temporal lobe atrophy, reduced glucose metabolism, and global amyloid burden. High‐risk status specifically upregulated complement C4a protein expression in postmortem brains. PageRank network analysis identified four candidate drugs targeting the APOE ‐containing astrocyte network. Experimental treatment with estradiol and levetiracetam significantly reduced APOE and complement C4 gene expression in hiPSC‐derived astrocytes. DISCUSSION By integrating cell‐based genetic risk with network‐level target prioritization, this framework enables robust patient stratification and experimental target validation.

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基于细胞的多基因风险评分预测阿尔茨海默病的临床进展并优先考虑基于网络的治疗靶点

背景：晚发性阿尔茨海默病（AD）表现出明显的生物学异质性。我们开发了一个框架，将细胞类型特异性多基因风险概况与AD的精准医学联系起来。方法在阿尔茨海默病神经影像学倡议（ADNI）和弗雷明汉心脏研究（FHS）队列中评估来自单核RNA - seq共表达网络的基于细胞的多基因风险评分（cbprs）。使用基于图的PageRank算法对网络枢纽进行优先排序，候选药物在人诱导多能干细胞（hiPSC）衍生的星形胶质细胞中进行验证。基于细胞的PRS分析确定了两个独立于网络细胞类型标记的遗传风险轴：载脂蛋白E （APOE）浓缩轴（Ast‐M2/Oli‐M45）和APOE独立轴（Ast‐M10/Oli‐M50），它们预测AD的加速进展（风险比：1.25-2.02），并与局部颞叶萎缩、葡萄糖代谢降低和整体淀粉样蛋白负担相关。高危状态在死后大脑中特异性上调补体C4a蛋白表达。PageRank网络分析确定了四种靶向含APOE星形胶质细胞网络的候选药物。实验中，雌二醇和左乙莱西丹显著降低了hiPSC来源的星形胶质细胞中APOE和补体C4基因的表达。通过整合基于细胞的遗传风险和网络水平的目标优先级，该框架能够实现稳健的患者分层和实验目标验证。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

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.