Abstract

Identifying genes that modify symptoms of Alzheimers 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.\n\nHighlightsO_LINew transgenic mouse population enables mapping of AD risk and resilience factors\nC_LIO_LITranscriptomic and phenotypic profiles in diverse AD mice parallel those in humans\nC_LIO_LIApoe genotype and expression correlate with cognitive symptoms in mice\nC_LIO_LITrpc3 is a novel target to reduce amyloid load and cognitive symptoms in AD\nC_LI