Summary Identifying genes that modify symptoms of Alzheimer’s disease (AD) will provide novel therapeutic strategies to prevent, cure or delay AD. To discover genetic modifiers of AD, we combined a mouse model of AD with a genetically diverse reference panel to generate F1 mice harboring identical ‘high-risk’ human AD mutations but which differ across the remainder of their genome. We first show that genetic variation profoundly modifies the impact of causal human AD mutations and validate this panel as an AD model by demonstrating a high degree of phenotypic, transcriptomic, and genetic overlap with human AD. Genetic mapping was used to identify candidate modifiers of cognitive deficits and amyloid pathology, and viral-mediated knockdown was used to functionally validate Trpc3 as a modifier of AD. Overall, work here introduces a ‘humanized’ mouse population as an innovative and reproducible resource for the study of AD and identifies Trpc3 as a novel therapeutic target. Highlights New transgenic mouse population enables mapping of AD risk and resilience factors Transcriptomic and phenotypic profiles in diverse AD mice parallel those in humans Apoe genotype and expression correlate with cognitive symptoms in mice Trpc3 is a novel target to reduce amyloid load and cognitive symptoms in AD

Systems genetics identifies modifiers of Alzheimer’s disease risk and resilience