Project Summary/ Abstract The mechanism underlying progressive memory loss and cognitive deterioration in Alzheimer’s disease (AD) is not fully understood and effective approaches to prevent or reverse memory deficits are unavailable. Here we show that augmentation of hippocampal neurogenesis in a mouse model of familial Alzheimer’s disease (FAD) reverses deficits in spatial recognition. Notably, new neurons are recruited into the memory circuit and serve as part of the engram during memory acquisition and retrieval. The number of new neurons in the engram of FAD mice is reduced compared to wild type. However, it is significantly increased following augmentation of neurogenesis. Importantly, new neurons encompass the majority of engram cells during memory retrieval. Thus, this project will test the hypothesis that new neurons play a major role in the engram and that increasing hippocampal neurogenesis in FAD restores the engram and rescues learning and memory. By manipulating levels of neurogenesis in FAD mouse models and using engram labeling techniques, experiments in Aim 1 will establish the role of new hippocampal neurons in the engram in FAD. Experiments in Aim 2 will determine the role of neurogenesis in memory retrieval in FAD. Aim 3 will unravel the signaling pathways underlying impaired hippocampal neurogenesis and engram function in AD. Aim 4 will examine the association between Alzheimer’s pathological hallmarks and the Engram. This program is designed to establish the role of hippocampal neurogenesis in cognitive deficits in AD and determine the efficacy of augmented neurogenesis in rescuing learning and memory in this disorder.