40 Hz light stimulation restores early brain dynamics alterations and associative memory in Alzheimer's disease model mice.

Visual gamma entrainment using sensory stimuli (vGENUS) is a promising non-invasive therapeutic approach for Alzheimer's disease (AD), showing efficacy in improving memory function. However, its mechanisms of action remain poorly understood. Using young AppNL-F/MAPT double knock-in (dKI) mice, a model of early AD, we examined brain dynamics alterations before amyloid plaque onset. High-density EEG recordings and metrics from fields outside neuroscience were used to assess brain dynamics fluidity-a measure of the brain's ability to transition between activity states. We revealed that dKI mice exhibit early, awake state-specific reductions in brain dynamics fluidity associated with cognitive deficits in complex memory tasks. Daily vGENUS sessions over 2 weeks restored brain dynamics fluidity and rescued memory deficits in dKI mice. Importantly, these effects built up during the stimulation protocol and persisted after stimulation ended, suggesting long-term modulation of brain function. Based on these results, we propose a "brain dynamics repair" mechanism for vGENUS that goes beyond current amyloid-centric hypotheses. This dual insight-that brain dynamics are both a target for repair and a potential diagnostic tool-provides new perspectives on early Alzheimer's disease pathophysiology.