Gonzales Mitzi M, Garbarino Valentina R, Kautz Tiffany F, Song Xuemei, Lopez-Cruzan Marisa, Linehan Leslie, Van Skike Candice E, De Erausquin Gabriel A, Galvan Veronica, Orr Miranda E, Musi Nicolas, He Yingxin, Bateman Randall J, Wang Chen-Pin, Seshadri Sudha, Kraig Ellen, Kellogg Dean
Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Commun Med (Lond). 2025 May 20;5(1):189. doi: 10.1038/s43856-025-00904-9.
Rapamycin has been shown to extend lifespan and acts on pathologies underlying Alzheimer's disease and related dementias in animal models. However, rapamycin's clinical application remains underexplored.
We conducted a single-site open-label phase 1 clinical trial (ClinicalTrials.gov: NCT04200911) to examine the effects of rapamycin in humans. Eligible participants were people 55-85 years old with mild cognitive impairment or early-stage dementia, which was defined as having a Global Clinical Dementia Rating Scale Score of 0.5-1. All participants received rapamycin (1 mg/day) for eight weeks. The primary aim was to evaluate rapamycin's central nervous system penetrance by assaying drug levels in the cerebrospinal fluid (CSF) before and after treatment. Secondary aims evaluated safety, cognition, Alzheimer's disease, and inflammatory biomarkers in the CSF and plasma.
In ten participants (mean age 74 ± 4 years, 60% female), we find that rapamycin is not detectable in the CSF before or after treatment. After treatment, we find that twenty, mostly mild adverse events occur, systolic blood pressure and hemoglobin A1c increase, multiple erythrocyte parameters decrease, and there are no significant cognitive changes. Furthermore, we find that CSF phosphorylated tau-181 (mean change (95% confidence interval) pg/ml), 2.64 [0.70-4.59]), glial fibrillary acidic protein (6262.21 [3787.44-9373.84]), and neurofilament light (367.19 [204.28-561.61]) and plasma interferon gamma (4.37 [3.01-5.74]), interleukin 5 (0.33 [0.12-0.64]), vascular endothelial growth factor D (3741.03 [1505.98-5976.07]), soluble fms-like tyrosine kinase-1 (258.88 [89.03-428.74]) and placental growth factor (20.81 [12.38-29.25]) significantly increase (FDR-corrected p-value < 0.05).
Rapamycin is not detectable in the CSF before or after treatment, but several Alzheimer's disease and inflammatory biomarkers increase after treatment. Our results highlight the need to better understand the biological effects and clinical impact of repurposing rapamycin for Alzheimer's disease.
已有研究表明雷帕霉素可延长寿命，并对动物模型中阿尔茨海默病及相关痴呆症的潜在病理过程产生作用。然而，雷帕霉素的临床应用仍有待深入探索。
我们开展了一项单中心开放标签的1期临床试验（ClinicalTrials.gov：NCT04200911），以研究雷帕霉素对人类的影响。符合条件的参与者为年龄在55至85岁之间、患有轻度认知障碍或早期痴呆症的人群，轻度认知障碍或早期痴呆症的定义为全球临床痴呆评定量表评分为0.5至1分。所有参与者接受雷帕霉素（1毫克/天）治疗八周。主要目的是通过检测治疗前后脑脊液（CSF）中的药物水平来评估雷帕霉素的中枢神经系统穿透性。次要目的是评估安全性、认知功能、阿尔茨海默病以及脑脊液和血浆中的炎症生物标志物。
在10名参与者（平均年龄74±4岁，60%为女性）中，我们发现治疗前后脑脊液中均未检测到雷帕霉素。治疗后，我们发现发生了20起主要为轻度的不良事件，收缩压和糖化血红蛋白A1c升高，多个红细胞参数降低，且认知功能无显著变化。此外，我们发现脑脊液中磷酸化tau-181（平均变化（95%置信区间）pg/ml），2.64 [0.70 - 4.59]）、胶质纤维酸性蛋白（6262.21 [3787.44 - 9373.84]）、神经丝轻链（367.19 [204.28 - 561.61]）以及血浆中的干扰素γ（4.37 [3.01 - 5.74]）、白细胞介素5（0.33 [0.12 - 0.64]）、血管内皮生长因子D（3741.03 [1505.98 - 5976.07]）、可溶性fms样酪氨酸激酶-1（258.88 [89.03 - 428.74]）和胎盘生长因子（20.81 [12.38 - 29.25]）显著升高（经错误发现率校正的p值<0.05）。
治疗前后脑脊液中均未检测到雷帕霉素，但治疗后几种阿尔茨海默病和炎症生物标志物升高。我们的结果凸显了有必要更好地了解将雷帕霉素重新用于治疗阿尔茨海默病的生物学效应和临床影响。
