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

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.

Fig. 1. Baseline to posttreatment changes in biomarkers of AD and related dementias biomarkers in plasma and cerebrospinal.

Baseline and post-treatment plasma (a–e) and cerebrospinal fluid (f–j) (N = 10 participants) biomarker changes were evaluated using paired samples t-tests or Wilcoxon signed rank tests. FDR-corrected p-values and color coding by participant are displayed. Mean difference from baseline to post-treatment (a) pTau-181: −0.22 pg/ml; (b) Aβ40: −8.56 pg/ml; c Aβ42: −0.668 pg/ml; (d) GFAP: −27.70 pg/ml; (e) NfL: 0.84 pg/ml; (f) pTau-181: 2.64 pg/ml; (g) Aβ40: 615.57 pg/ml; (h) Aβ42: 21.51 pg/ml; (i) GFAP: 6,262.21 pg/ml; and (j) NfL: 367.19 pg/ml. ADRD Alzheimer’s disease and related dementias, p-tau phosphorylated tau, Aβ amyloid beta, GFAP glial fibrillary acidic protein, NfL neurofilament light.

Fig. 2. Baseline to posttreatment changes in inflammatory biomarkers in plasma.

Baseline and post-treatment plasma biomarker (a–e) (N = 10 participants) changes were evaluated using paired samples t-tests or Wilcoxon signed rank tests. FDR-corrected p-values and color coding by participant are displayed. Mean difference from baseline to post-treatment. a INF-γ: 4.38 pg/ml; (b) IL−5: 0.33 pg/ml; (c) VEGF-D: 3741.0 pg/ml; (d) sFlt1: 258.88 pg/ml; (e) PIGF: 20.81 pg/ml. IFN‐γ interferon gamma, IL interleukin, VEGF vascular endothelial growth factor, sFLT-1 soluble fms-like tyrosine kinase, PIGF placental growth factor.