人体没有”减少50%老年痴呆的发病率“的效果，只是说发现两个数据库中”服用该药与痴呆发病率的下降有关“，这是摘要

摘要

阿尔茨海默病 (AD) 遗传、病理和临床异质性证据对传统药物开发提出了挑战。我们对治疗载脂蛋白 E4 (APOE4) 相关 AD 的药物进行了计算药物再利用筛选。我们首先通过分析公开可用的人脑数据库建立了 AD 的 APOE 基因型依赖性转录组特征。然后，我们根据 Connectivity Map 数据库查询这些特征，该数据库包含 1,300 多种药物的转录组扰动，以确定那些最能逆转 APOE 基因型特异性 AD 特征的药物。布美他尼被选定为 APOE4 相关 AD 的最佳药物。使用布美他尼治疗无或有淀粉样蛋白 β (Aβ) 积累的 APOE4 敲入小鼠可挽救电生理、病理或认知缺陷。单细胞RNA 测序揭示了这些小鼠特定细胞类型中 AD 特征的转录组学逆转，这一发现在 APOE4 诱导的多能干细胞 (iPSC) 衍生神经元中得到证实。在人类中，在两个电子健康记录数据库中，布美他尼服用与 65 岁以上个体的 AD 患病率显著降低有关，提示布美他尼在预防 AD 中的有效性

Abstract

The evident genetic, pathological and clinical heterogeneity of Alzheimer’s disease (AD) poses challenges for traditional drug development. We conducted a computational drug-repurposing screen for drugs to treat apolipoprotein E4 (APOE4)-related AD. We first established APOE genotype-dependent transcriptomic signatures of AD by analyzing publicly available human brain databases. We then queried these signatures against the Connectivity Map database, which contains transcriptomic perturbations of more than 1,300 drugs, to identify those that best reverse APOE genotype-specific AD signatures. Bumetanide was identified as a top drug for APOE4-related AD. Treatment of APOE4-knock-in mice without or with amyloid β (Aβ) accumulation using bumetanide rescued electrophysiological, pathological or cognitive deficits. Single-nucleus RNA sequencing revealed transcriptomic reversal of AD signatures in specific cell types in these mice, a finding confirmed in APOE4 induced pluripotent stem cell (iPSC)-derived neurons. In humans, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 years in two electronic health record databases, suggesting the effectiveness of bumetanide in preventing AD.