Alzheimer's disease (AD) is a debilitating brain disorder, with staggering human and financial cost in a rising aging population, and the complexity of the disease's underlying pathophysiology presents a major challenge in developing therapeutics. Recently, in an approach that we term Gamma ENtrainment Using Sensory stimuli (GENUS), we found that neural oscillations in the gamma frequency range (30-90 Hz) could be induced to impact pathology in AD mouse models by exposing them to flickering light at 40 Hz or 40 Hz train of auditory pure tone. We found that GENUS reduces amyloid burden and hyperphosphorylated tau in respective amyloid and tauopathy mouse models, as well as modifies microglia, astrocytes and vasculature. We also show that multimodal GENUS can be applied with simultaneous auditory and visual stimulation, and prolonged visual GENUS promises longer-lasting effects. Further, we report reduced AD pathology not only in the primary sensory cortex but also in the hippocampus and medial prefrontal cortex. Thus, the goal of our proposed research is to determine the efficacy and durability of multimodal GENUS and whether the beneficial effects of multimodal GENUS can be modulated by AD-related drug treatments and AD-risk carrier of APOE. To this end, we will systematically characterize the temporal profile of chronic multimodal GENUS (1 or 2 h/day) and determine the decay time of post-GENUS in amyloid and tau mouse models. We hypothesize that chronic multimodal GENUS for 6 weeks may impact different brain areas for longer periods. We will assess whether FDA approved drugs could modulate and enhance the longer-lasting decay time of post-GENUS after 6 weeks of multimodal GENUS. We will test an acetylcholinesterase inhibitor, an NMDA receptor antagonist, and an antiepileptic drug combined with chronic multimodal GENUS. APOE4 is the highest risk gene for sporadic AD, and ~40% of the global AD population carries at least one copy of APOE4. As such, we will investigate how APOE4 modifies GENUS response. Our recent studies show that GENUS impacts neurons, microglia, astrocytes and the vasculature, all of which are associated with APOE. We will use humanized APOE-knock in mice and APOE-knock in mice crossed with amyloid and tauopathy mouse models to determine whether APOE can modify the response to GENUS.