Alzheimer's disease and the therapeutic potential of theta burst stimulation: A systematic review of preclinical and clinical studies

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral impairment. Despite growing research efforts, effective disease-modifying interventions remain elusive. Theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation (rTMS), has shown promise in modulating cortical excitability, synaptic plasticity, and neuroprotective mechanisms. This systematic review aimed to evaluate the efficacy and safety of TBS in AD by synthesizing findings from preclinical and clinical studies. Methods: A systematic search of PubMed, Scopus, Embase, Web of Science, and the Cochrane Library was conducted up to January 2025. Studies investigating TBS, including intermittent TBS [iTBS] and continuous TBS [cTBS], in human patients with AD or in animal models of AD were included. Primary outcomes included cognitive function and neuropsychiatric symptoms. Secondary outcomes included biomarkers of neuroplasticity and neurodegeneration. The risk of bias was assessed using the Joanna Briggs Institute (JBI) and Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tools. Results: Twenty studies met the inclusion criteria, comprising six preclinical and 14 clinical studies. Preclinical evidence suggests that TBS reduces amyloid-beta deposition, enhances synaptic plasticity, mitigates neuroinflammation and oxidative stress, and improves cognitive performance in animal models of AD. iTBS targeting the dorsolateral prefrontal cortex (DLPFC) improved cognitive function, depression, anxiety, and activities of daily living, with some studies reporting non-significant findings in specific neuropsychological assessments. Neuroplasticity changes were observed in motor-evoked potentials and resting motor thresholds, with lower responses in patients with AD and variable reproducibility over time. Additionally, structural and functional brain changes, including preserved hippocampal volume and enhanced frontal beta activity, were associated with cognitive improvements. Adverse events were mild and well- tolerated. Conclusion: Preclinical studies robustly support the neuroprotective and neuropsychiatric effects of TBS in AD models. Clinical findings suggest possible benefits of TBS, particularly iTBS over the DLPFC; however, clinical results are inconsistent and limited by small sample sizes and protocol variability. These findings highlight the challenges of translating animal data to humans and underscore the need for larger, controlled randomized clinical trials to confirm safety and efficacy and optimize treatment parameters.