Systematic Review and Meta-Analysis Confirm the Moderate Efficacy of High-Frequency r-TMS in Alzheimer's Disease: Mediating Effects of Anhedonia-Apathy and Add-On Motor-Cognitive Excersizes.

Objectives: Alzheimer's disease (AD) presents a major global health issue of significant socio-economic impact. Pharmacological treatments for AD have limited efficacy, prompting the exploration of alternative therapies, such as repetitive transcranial magnetic stimulation (rTMS), a promising non-invasive technique to enhance cognitive function in AD patients. Our systematic review and meta-analysis aim to evaluate the efficacy of rTMS in relation to cognitive function in AD patients, identify optimal rTMS stimulation parameters, and understand the underlying neural mechanisms.
Methods: We conducted a comprehensive literature search in PubMed using predefined search terms to identify original research articles investigating the effects of rTMS on cognitive function in AD patients. We selected only randomized controlled trials (RCTs) with sufficient quantitative data for comparing active rTMS to the sham-coil treatment, and then performed a random effects meta-analysis using standardized mean differences (SMDs) to synthesize the effects across studies.
Results: The systematic review included 22 studies, among which 14 RCTs met our criteria for meta-analysis. High-frequency rTMS, particularly targeting the dorsolateral prefrontal cortex (DLPFC), evoked significant cognitive improvements in AD patients, with a moderate positive effect size of rTMS on cognitive function (Hedges' g=0.580, 95% CI [0.268, 0.892], p<0.001), albeit with substantial heterogeneity (I ^² =59%). Funnel plot asymmetry and Egger's test suggested a potential publication bias, but fail-safe N analysis indicated a robust finding. Moreover, anhedonia-apathy symptoms and motor-cognitive exercises mediated the efficacy of tTMS in ameliorating cognitive functioning across several studies.
Conclusion: rTMS demonstrates moderate efficacy in improving cognitive function in AD-patients, most distinctly with high-frequency rTMS stimulation protocols targeting the DLPFC area. The meta-analysis support rTMS as a viable therapeutic intervention for cognitive enhancement in AD. Future promising research should focus on personalized treatment strategies targeting mediating factors, baseline connectivity patterns, and TMS-induced neuroplasticity in AD.