Genetic studies show that the bridging integrator 1 (BIN1) gene is a major Alzheimer’s disease (AD) susceptibility gene, second only to APOE. Recent whole-exome sequencing (WES) analyses have identified RIN3 (Ras and Rab interactor 3) as an AD-risk gene. The BIN1 protein directly interacts with the RIN3 protein to initiate the internalization of beta-amyloid precursor protein (APP). This is the first step in the beta-secretase (BACE1)-mediated processing of APP that ultimately results in the generation of amyloid beta, the key component of the plaques that characterize the pathology of AD. Our recent in vitro studies have shown that the neuronal form of BIN1, but not the nonneuronal form, lowered amyloid beta production, and that this required RIN3. Despite their importance as genetic risk factors for AD, the specific role of BIN1 and/or RIN3 in the disease process remains largely unknown. Here, we plan to use an integrated approach employing a 3D human neural cell culture model, human-derived induced pluripotent stem cells (hiPSCs) and animal models to address the central hypothesis that RIN3-BIN1 interaction in the neurons regulates the internalization of APP to modulate BACE1-mediated processing and amyloid beta production. We think our proposal will provide the blueprint for the development of potential therapeutic strategies for early- or late-stage AD by targeting RIN3-BIN1 interaction in neurons.