Reelin signaling enhances hippocampal synaptic plasticity and increasing evidence suggests Reelin serves a neuroprotective role in Alzheimer’s disease (AD). Reelin delays AD hallmarks including amyloid plaque formation, tau hyperphosphorylation, and cognitive deficits, contributing to remarkable resilience against AD. Reelin’s ability to enhance synaptic plasticity is dependent on its obligate APOER2/VLDLR receptors that are prone to high degree of alternative splicing. We uncovered a diverse range of human full-length APOER2 splice transcripts in postmortem AD brains and age-matched controls. Most of the splicing events occur in functionally important domains such as the ligand-binding domains where Reelin binds suggesting variation in ligand-receptor interactions and functional consequences related to Reelin signaling; however, this has not been explored. The project includes three aims. Aim 1 seeks to determine if alternative splicing of APOER2 and VLDLR, the obligate receptors of Reelin, impacts AD risk. Aim 2 will assess the functional consequences of receptor splice variants on Reelin binding and signaling, proposing that specific interactions may either protect against or increase AD risk. Finally, Aim 3 will explore the mechanism of Reelin's resilience in AD-associated tau pathology, utilizing a CRISPR activation strategy to increase endogenous Reelin expression with the goal of reversing tau pathology-related deficits. This project, poised to deliver high-impact insights of resilient AD genes and promising therapeutics in the AD field.