High intensity 40 Hz flicker improves amyloid pathology and cognition with autophagy in 3xTg mice

Summary Gamma-frequency (40 Hz) flicker stimulation has emerged as a noninvasive approach for modulating Alzheimer's disease (AD)-related pathology, yet the influence of stimulation intensity remains unclear. We examined whether visual 40 Hz stimulation at different light intensities elicits distinct neurobiological effects in 19–24-week-old 3xTg-AD mice. High-intensity stimulation (1100–1500 lux) improved cognitive performance, modulated AMPK/mTOR signaling and autophagy-related markers, reduced neuronal Aβ burden, and preserved synaptic and neuronal integrity in both the primary visual cortex and hippocampus. In contrast, low-intensity stimulation (100–500 lux) primarily induced molecular changes in the primary visual cortex, with limited effects on hippocampal pathology or cognition. Pharmacological inhibition of autophagy with 3-methyladenine attenuated these effects. Together, these findings suggest graded responses to visual 40 Hz stimulation within the tested intensity range and implicate stimulation intensity as a contributing factor to region-specific and cognitive outcomes in early-stage AD models.