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Brain Cell-based Genetic Subtyping and Drug Repositioning for Alzheimer Disease.

medRxiv : the preprint server for health sciences(2024)

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Abstract
Alzheimer's Disease (AD) is characterized by its complex and heterogeneous etiology and gradual progression, leading to high drug failure rates in late-stage clinical trials. In order to better stratify individuals at risk for AD and discern potential therapeutic targets we employed a novel procedure utilizing cell-based co-regulated gene networks and polygenic risk scores (cbPRSs). After defining genetic subtypes using extremes of cbPRS distributions, we evaluated correlations of the genetic subtypes with previously defined AD subtypes defined on the basis of domain-specific cognitive functioning and neuroimaging biomarkers. Employing a PageRank algorithm, we identified priority gene targets for the genetic subtypes. Pathway analysis of priority genes demonstrated associations with neurodegeneration and suggested candidate drugs currently utilized in diabetes, hypertension, and epilepsy for repositioning in AD. Experimental validation utilizing human induced pluripotent stem cell (hiPSC)-derived astrocytes demonstrated the modifying effects of estradiol, levetiracetam, and pioglitazone on expression of APOE and complement C4 genes, suggesting potential repositioning for AD.
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要点】:本文通过基于细胞的共调节基因网络和多基因风险评分方法,对阿尔茨海默病进行了基因亚型划分和药物再定位,创新性地提出了针对AD的基因亚型和潜在治疗靶点。

方法】:研究采用了一种新颖的方法,利用基于细胞的共调节基因网络和多基因风险评分(cbPRSs)来定义基因亚型。

实验】:通过PageRank算法识别了针对基因亚型的优先基因靶点,并对人类诱导的多能干细胞(hiPSC)来源的星形胶质细胞进行实验验证,发现estradiol、levetiracetam和pioglitazone对APOE和补体C4基因表达具有调节作用,提示这些药物在AD治疗中的潜在再定位可能。