Rapamycin treatment for Alzheimer’s disease and related dementias: a pilot phase 1 clinical trial

作者：Mitzi M. Gonzales, Valentina R. Garbarino, Tiffany F. Kautz, Xuemei Song, Marisa Lopez‐Cruzan, Leslie A. Linehan, Candice E. Van Skike, Gabriel A. de Erausquin, Verónica Galván, Miranda E. Orr, Nicolas Musi, Yingxin He, Randall J. Bateman, Chen‐Pin Wang, Sudha Seshadri, Ellen Kraig, Dean L. Kellogg · 发表于：Communications Medicine · 年份：2025 · DOI：10.1038/s43856-025-00904-9 · 被引用次数：41 · 研究领域：Alzheimer's disease research and treatments、Dementia and Cognitive Impairment Research、Amyotrophic Lateral Sclerosis Research

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...