A compound pulsed magnetic field achieves superior cognitive benefits against Alzheimer's disease progression via multi-level restoration of neural oscillations and cerebral perfusion.

The link between impaired gamma oscillations and Alzheimer's disease (AD) has inspired therapies using rhythmic physical stimuli. However, given that cognition requires cross-frequency interactions like theta-gamma coupling, single-frequency stimulation may yield limited benefits. This study therefore applied a compound pulsed magnetic field (cPMF) with theta rhythm-modulated gamma frequency to evaluate its efficacy and mechanisms against AD pathology compared with single gamma-frequency pulsed magnetic field (sPMF). Local field potential results showed that cPMF outperformed sPMF by significantly enhancing hippocampal oscillations and particularly rescuing the impaired theta-gamma phase-amplitude coupling in AD mice, which was positively correlated with improved cognitive performance in behavioral tests. Correspondingly, cPMF treatment enhanced blood flow perfusion in the prefrontal and cerebral cortices of AD mice, which may contribute to amyloid-β clearance and neuroinflammation attenuation. At the molecular level, cPMF rescued AD-related transcriptional alterations by upregulating key genes involved in cholinergic signaling (Chat, Chrm1), glymphatic function (Aqp4), and synaptic plasticity (Gria1, an AMPA receptor subunit). These findings indicated that cPMF stimulation achieved multi-level restorative effects by enhancing neuronal activity, promoting cerebral perfusion, facilitating amyloid-β clearance, and rectifying aberrant gene expression, ultimately leading to cognitive improvement in AD mice. This cPMF stimulation paradigm highlights the therapeutic potential of targeting endogenous oscillatory interactions for treating neurological disorders.