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

Abstract

Visual gamma entrainment using sensory stimuli (vGENUS) is a promising non-invasive therapeutic approach for Alzheimers 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 novel metrics from fields outside neuroscience were used to assess brain dynamics fluidity--a measure of the brains 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 two 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 Alzheimers disease pathophysiology. Significance StatementGamma ENtrainment Using Sensory stimuli (GENUS), involving 40 Hz rhythmic sensory stimulation, shows promise in improving memory function in Alzheimers disease (AD). We hypothesized that brain dynamics changes could be detected before plaque onset and modulated by vGENUS. Applying techniques from climate science to EEG recordings in young AD model mice, we found reduced brain dynamics fluidity associated with early cognitive deficits. Two weeks of vGENUS restored brain dynamics and improved memory, with effects persisting post-treatment. These findings challenge the amyloid-centric view of AD, introduce a potential early biomarker, and suggest vGENUS acts by "repairing" brain dynamics. Our approach offers new perspectives on early diagnosis and non-invasive interventions for AD and other neurological disorders with disrupted brain dynamics.