Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.