阿尔茨海默病是发病缓慢、随着时间不断恶化的多因素神经退化病变，占痴呆成因的六至七成，其特征是不同类型细胞存在多种基因表达复杂变化，这给治疗带来巨大困难，过去20多年开展超过2700项临床研究仅有3种靶向新药获得批准上市，其中1种不能有效减缓痴呆症状而于2024年退市。
2025年7月21日，全球自然科学三大旗舰期刊之一、美国《细胞》正刊发表旧金山加利福尼亚大学和格莱斯顿研究院的研究报告，将阿尔茨海默病的基因表达特征与现有药物引起的基因表达变化进行比较，筛选出2种抗癌老药联合治疗有望逆转阿尔茨海默病期间大脑发生的基因表达变化，可能减缓甚至逆转痴呆症状。
该研究利用人工智能计算工具，首先从3项阿尔茨海默病大脑研究获取公开数据，分析已故志愿者（无论是否患有阿尔茨海默病）大脑单个细胞基因表达变化特征。
再对已经获得美国食品药品监督管理局批准的1300种现有药物进行分析，寻找其中哪些药物能够逆转阿尔茨海默病神经细胞以及神经胶质细胞基因表达变化，发现86种药物能够逆转一种细胞的阿尔茨海默病基因表达特征，25种药物能够逆转多种细胞的阿尔茨海默病基因表达特征，但是目前只有10种药物已经获得批准用于人体。
随后，对洛杉矶加利福尼亚大学医疗数据库140万例65岁以上患者数百万份电子病历进行分析，最后发现其中5种药物治疗后，患者的阿尔茨海默病发生比例显著较低。
最后，对携带多种阿尔茨海默病相关基因突变、随着年龄增长出现类似阿尔茨海默病的小鼠进行测试，结果发现1996年获得批准用于治疗乳腺癌的来曲唑可以治疗阿尔茨海默病神经细胞、1998年获得批准用于治疗结直肠癌的伊立替康可以治疗阿尔茨海默病神经胶质细胞，两药联合可以消除病情进展期间出现的神经细胞以及神经胶质细胞基因表达特征，减少毒性蛋白质团块形成，显著减缓小鼠大脑退化，甚至可以恢复小鼠记忆能力。
因此，该研究结果表明，细胞类型靶向联合治疗对阿尔茨海默病等多因素复杂疾病大有希望，并为针对患者特定基因表达和临床特征的精准治疗奠定基础。预计该研究将很快从实验室进入临床试验阶段，以便能够直接对人类阿尔茨海默病患者测试该联合治疗，希望能够迅速转化为全球数千万阿尔茨海默病患者的真正解决方案，并为乳腺癌等恶性肿瘤治疗带来老药再利用新思路。
Cell. 2025 Jul 21. IF: 42.5
Cell-type-directed network-correcting combination therapy for Alzheimer’s disease.
Yaqiao Li, Carlota Pereda Serras, Jessica Blumenfeld, Min Xie, Yanxia Hao, Elise Deng, You Young Chun, Julia Holtzman, Alice An, Seo Yeon Yoon, Xinyu Tang, Antara Rao, Sarah Woldemariam, Alice Tang, Alex Zhang, Jeffrey Simms, Iris Lo, Tomiko Oskotsky, Michael J. Keiser, Yadong Huang, Marina Sirota.
University of California, San Francisco, San Francisco, CA, USA; Gladstone Institutes, San Francisco, CA, USA; University of California, Berkeley, Berkeley, CA, USA.
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Human transcriptomic and drug repurposing analyses identify letrozole and irinotecan for AD
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Real-world EMR data reveal lower AD risks in patients exposed to letrozole or irinotecan
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Letrozole and irinotecan combination therapy improves memory and pathology in AD models
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Transcriptomic reprogramming represents a promising strategy for treating complex diseases
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by heterogeneous molecular changes across diverse cell types, posing significant challenges for treatment development. To address this, we introduced a cell-type-specific, multi-target drug discovery strategy grounded in human data and real-world evidence. This approach integrates single-cell transcriptomics, drug perturbation databases, and clinical records. Using this framework, letrozole and irinotecan were identified as a potential combination therapy, each targeting AD-related gene expression changes in neurons and glial cells, respectively. In an AD mouse model with both Aβ and tau deposits, this combination therapy significantly improved memory performance and reduced AD-related pathologies compared with vehicle and single-drug treatments. Single-nucleus transcriptomic analysis confirmed that the therapy reversed disease-associated gene networks in a cell-type-specific manner. These results highlight the promise of cell-type-directed combination therapies in addressing multifactorial diseases like AD and lay the groundwork for precision medicine tailored to patient-specific transcriptomic and clinical profiles.
KEYWORDS: Alzheimer’s disease, amyloid pathology, connectivity map, drug repurposing, electronic medical record, irinotecan, letrozole, mouse model, single-cell transcriptome, tau pathology
DOI: 10.1016/j.cell.2025.06.035
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