Evaluation Of Rapamycin As A Neuroprotective Treatment In Alzheimer’s Disease: A Six-Month Single-Arm Open-Label Clinical Pilot Trial

Research Summary

An open-label, single-arm pilot trial asking whether six months of weekly oral rapamycin is feasible, tolerable and biologically active in people with early-stage Alzheimer’s disease.

Who Or What Was Studied?

Fourteen adults aged 51-67 (mean 60.6; 8 women, 6 men) with amyloid-confirmed mild cognitive impairment (6) or mild dementia of Alzheimer’s type (8), recruited at a memory clinic in Stockholm. They took oral rapamycin (Rapamune) starting at 3 mg per week and raised to 7 mg per week from the second week, for 26 weeks; 13 of the 14 completed treatment. There was no placebo group, and every participant was also taking a cholinesterase inhibitor.

What Did The Research Show?

• The primary outcome — brain glucose metabolism measured by [18F]FDG PET in the posterior cingulate cortex, precuneus and temporoparietal cortex — did not change significantly over 26 weeks (Ki changes ranged from -1.0% to +0.6%).
• Exploratory regions did increase: putamen +2.5%, insula +2.1% and anterior cingulate cortex +2.3% in SUVR, and thalamic blood flow rose 7.5%.
• Higher whole-blood rapamycin concentrations correlated with larger increases in [18F]FDG SUVR in several regions, including the temporoparietal cortex (r = 0.68, p = 0.02).
• No serious adverse events occurred; the commonest side effects were diarrhoea (6/14), nausea (2/14) and mouth sores (3/14), all mild or moderate and resolved.
• Cerebrospinal fluid total tau rose 21.8% and neurofilament light rose 23.5%, while p-tau181 was unchanged, so the p-tau/total tau ratio fell 14.1%. Cognitive scores and total grey matter volume were largely unchanged over the six months.

Limitations And Interpretation

• Single-arm with no placebo: the observed changes cannot be separated from natural disease progression or regression to the mean.
• Only 13 participants completed the trial, which limits the statistical power to detect modest effects.
• The report is a medRxiv preprint that has not been certified by peer review; the authors describe it as hypothesis-generating rather than definitive.
• Baseline lumbar punctures and cognitive tests were done during routine diagnostic work-up months before treatment began, which complicates interpretation of the cerebrospinal fluid results.