rTMS modulates early AD progression via synergistic brain network reorganization and peripheral biomarker dynamics

Repetitive transcranial magnetic stimulation (rTMS) improves cognition in Alzheimer's disease (AD), yet its biomarker and neuroplasticity effects remain unclear. Cognitive scale scores, plasma biomarker levels, and resting-state fMRI brain network in AD patients were analyzed before and after a 14-day 20 Hz rTMS intervention. The results demonstrated that rTMS intervention significantly improved cognitive performance (MMSE: Z =  - 2.863, q = 0.017; MoCA: t =  - 6.137, q < 0.001; RAVLT_I: t =  - 3.436, q = 0.011) and reduced neuropsychiatric symptoms (NPI: Z =  - 2.547, q = 0.037; HAMD: Z =  - 3.472, q = 0.009). A 9.4% reduction in neurofilament light chain levels was demonstrated (Z =  - 2.371, P = 0.018), with baseline p-Tau181 levels being inversely correlated to Aβ42 changes (R =  - 0.428, P = 0.033). Enhanced global efficiency (GE: t =  - 1.865, P = 0.081, r = 0.423) and increased connection density (CD: Z =  - 1.823, P = 0.068, r = 0.442) were identified in neural networks. Notably, GE improvements positively correlated with elevated Aβ42/40 (R = 0.596, P = 0.025), while cognitive gains measured by the MoCA were significantly associated with network reorganization metrics (GE: R = 0.486, P = 0.048; CD: R = 0.514, P = 0.035). rTMS demonstrates potential in mitigating neurodegeneration by enhancing brain network integration and modulating Aβ metabolism. This effect was particularly pronounced in early-stage AD patients who exhibit preserved neural integrity. These findings advance therapeutic assessment frameworks and decode TMS neuromodulation mechanisms. The trial was prospectively registered (ChiCTR2400080657, ClinicalTrials.gov; 2024-02-04).