OBJECTIVE: The 5xFAD mouse model of Alzheimer disease (AD) recapitulates amyloid-beta (Aβ) deposition and pronounced seizure susceptibility observed in patients with AD. Forty-hertz audiovisual stimulation is a noninvasive technique that entrains gamma neural oscillations and can reduce Aβ pathology and modulate glial expression in AD models. We hypothesized that 40-Hz sensory stimulation would improve seizure susceptibility in 5xFAD mice and this would be associated with reduction of plaques and modulation of glial phenotypes. METHODS: 5xFAD mice and wild-type (WT) littermates received 1 h/day 40-Hz audiovisual stimulation or sham (n = 7-11/group), beginning 2 weeks before and continuing throughout amygdala kindling epileptogenesis. Postmortem analyses included Aβ pathology and morphology of astrocytes and microglia. RESULTS: 5xFAD mice exhibited enhanced susceptibility to seizures compared to WT, evidenced by fewer stimulations to reach kindling endpoint (incidence rate ratio [IRR] = 1.46, p <
.0001) and a trend to higher seizure severity (odds ratio [OR] = .34, p = .059). Forty-hertz stimulation reduced the behavioral severity of the first seizure (OR = 4.04, p = .02) and delayed epileptogenesis, increasing the number of stimulations required to reach kindling endpoint (IRR = .82, p = .01) compared to sham, regardless of genotype. 5xFAD mice receiving sensory stimulation exhibited ~50% reduction in amyloid pathology compared to sham. Furthermore, markers of astrocytes and microglia were upregulated in both genotypes receiving 40-Hz stimulation. SIGNIFICANCE: Forty-hertz sensory entrainment slows epileptogenesis in the mouse amygdala kindling model. Although this intervention improves Aβ pathology in 5xFAD mice, the observed antiepileptogenic effect may also relate to effects on glia, because mice without Aβ plaques (i.e., WT) also experienced antiepileptogenic effects of the intervention.