Deregulation of Synaptic Plasticity-Related MicroRNAs After Repetitive Transcranial Magnetic Stimulation in Alzheimer’s Disease

Repetitive transcranial magnetic stimulation (rTMS) is an emerging non-invasive therapeutic approach to slow down cognitive and functional decline in Alzheimer's disease (AD), potentially through plasticity-related mechanisms. MicroRNAs (miRNAs) play a crucial role in synaptic plasticity, and their deregulation contributes to AD-related cognitive impairment. In the present study, we first used a dosimetric model to translate rTMS field applied in AD patients to an in vitro system, identifying miRNAs as potential biomarkers responsive to rTMS. We found that rTMS induced in vitro deregulation of miR-26b, miR-125b, miR-181c, and miR-146a. Then, we investigated the effects of rTMS over precuneus during a 3-week, randomized, sham-controlled trial in AD patients. In patient serum, miR-26b, miR-30b, and miR-125b were significantly modulated in AD patients compared to healthy controls, though no significant modulation emerged between sham and rTMS groups before or after stimulation. Subsequently, the correlation analyses, which incorporated patients' cognitive scores, revealed that reduced miR-25 levels were significantly associated with cognitive improvement. However, no significant differences emerged between Real- and sham-rTMS correlation coefficients, likely due to the limited sample size, indicating that miR-25 may represent a general prognostic marker rather than a treatment-specific indicator. Furthermore, the ability of this miRNA to discriminate responders from non-responders, shown by ROC analysis, highlights its potential as a promising predictor of rTMS treatment efficacy to be validated in a larger patient cohort. Altogether, our findings suggest, for the first time, that rTMS may modulate specific miRNAs in AD patients, with miR-25 representing a pivotal key target for future validation studies.