Evaluation of rapamycin as a neuroprotective treatment in Alzheimer's disease: a six-month single-arm open-label clinical pilot trial

BackgroundRapamycin has demonstrated neuroprotective effects in preclinical Alzheimers disease (AD) models, yet clinical data remain limited. Here, we conducted a pilot trial to assess the feasibility and safety of rapamycin treatment in early-stage AD using multimodal neuroimaging and cerebrospinal fluid (CSF) biomarkers. MethodsThis single-arm, open-label pilot study enrolled 14 participants with early-stage AD who received oral rapamycin 7 mg weekly for 26 weeks. Thirteen participants completed treatment. The primary outcome was change in cerebral glucose metabolism measured by [18F]FDG PET (Ki and SUVR) in pre-specified regions commonly affected in AD: posterior cingulate cortex, precuneus, and temporoparietal cortex. Secondary outcomes included cerebral blood flow (CBF) via ASL MRI, CSF biomarkers, volumetric MRI, and cognition. ResultsRapamycin was well tolerated, with no serious adverse events. No significant metabolic or perfusion changes were observed in primary regions. Exploratory analyses showed increases in [18F]FDG SUVR in the putamen, insula, and anterior cingulate cortex, and thalamic CBF. Higher rapamycin blood concentrations correlated with increased [18F]FDG SUVR in several regions, including the temporoparietal cortex. CSF analysis demonstrated significant increases in total tau, neurofilament light, A{beta}40, and a numerical, non-significant increase in A{beta}42 of similar effect size, while p-tau remained largely unchanged, resulting in a significantly decreased p-tau/total tau ratio. ConclusionsThis pilot study demonstrates feasibility of rapamycin trials in AD. The primary [18F]FDG outcomes showed no decline, and even increases in exploratory regions, in contrast to what would be expected from natural disease progression. The observed elevations in CSF biomarkers warrant further investigation.