Gamma Sensory Flicker as an Early Intervention for Alzheimer's Disease: Mechanisms and Protective Effects Alzheimer's disease (AD) requires a new therapeutic approach to intervene prior to or early in the disease. In the previous funding period, the PI and team discovered that gamma, or 40Hz, sensory flicker (lights and sounds turning on and off with millisecond precision) has beneficial effects in mouse models of Alzheimer's pathology at symptomatic stages. Gamma flicker drove gamma neural activity, reduced amyloid plaques, recruited microglia to engulf amyloid beta (Aβ), and restored memory behavior in mice with Aβ pathology. This proposal marks the exciting shift of this research to intervene in AD during the preclinical stages prior to plaque accumulation and the onset of memory deficits. Microglia and cytokines play a disease modifying role in AD and affect network function, with potential damaging or beneficial effects. Recent research, from our team and others, reveals protective immune gene and protein signatures in early AD pathogenesis. The goal of this proposal is to determine how flicker stimulation affects protective immune function in preclinical AD stages to improve neural signatures of memory and to elucidate the mechanisms of these effects. Using cutting edge transcriptomic and proteomic analyses and large-scale neural recordings, we will determine the effects of flicker on microglia phenotypes and neural signatures of memory. Using pharmacological and genetic manipulations, we will determine the causal role of microglia and microglial signaling in mediating flicker's effects on microglia phenotype and network function. We will determine if flicker-induced microglia gene transcription overlaps with recently defined human anti-inflammatory microglia markers present in early AD, using our teams' discoveries from cutting edge cell-type specific analysis of human tissue. Aim 1 will define the effects of flicker on microglia phenotype at preclinical stages, the molecular mechanisms involved, and the human-relevant transcriptional effects. Aim 2 will establish how preclinical flicker affects neural signature of memory integration during learning and the causal role of microglia in this process. This research will result in a paradigm shift to use noninvasive brain stimulation prophylactically in people at risk of AD prior to plaques or symptoms. Furthermore, this research will reveal new mechanisms by which flicker stimulation promotes protective immune function and promotes memory.