Effects of cerebellar intermittent theta-burst stimulation on patients with Alzheimer's disease: A randomized controlled trial

Background The cerebellum plays a crucial role in cognitive processing, making it a potential target for therapeutic intervention in Alzheimer's disease (AD). Objective This study aimed to investigate the effect of cerebellar intermittent theta-burst stimulation (iTBS) in patients with AD. Methods We conducted a randomized, double-blind, sham-controlled clinical trial in which patients were randomly allocated to receive either active-iTBS or sham-iTBS. The primary outcome was the change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores from baseline to week 4. Secondary outcomes included evaluations of neurophysiological measures, brain network functions, and glymphatic clearance. Results From April 20 to June 25, 2024, 20 patients were analyzed. Compared with sham-iTBS, active-iTBS significantly improved cognition at week 4, indicated by reduced CDR-SB scores (mean changes: −0.60 versus 0.15; adjusted β: 0.73; 95% CI, 0.17–1.26). In the active-iTBS group compared with the sham-iTBS group, the power spectral density in electroencephalogram revealed global decreased in theta power (adjusted β, −0.014; 95% CI, −0.024–0.003) and increased beta power (adjusted β, 0.002; 95%CI, 0.000–0.005), the functional magnetic resonance imaging demonstrated enhanced the gradient values of default mode network activity along the principal gradient, and the structural magnetic resonance imaging indicated an improvement in glymphatic clearance (adjusted β, 0.097, 95% CI, 0.0381–0.1603). Conclusions A four-week course of iTBS improved cognitive function in patients with AD, possibly via promoting the Beta frequency band power, enhancing brain network functionality, and facilitating glymphatic clearance. Trial registration ClinicalTrials.gov (NCT06379100, April 14, 2024).