DISCOVERING GENETIC MODIFIERS OF ALZHEIMER’S DISEASE USING NOVEL MOUSE MODELS

Abstract

Recent studies of familial AD cases suggest genetic factors can delay the onset and progression of cognitive deficits by decades. Therefore, these genetic factors may provide key targets for treatment and prevention of AD. However, significant barriers restrict our ability to discover the genetic mechanisms of resilience using conventional approaches. Resilient individuals are often asymptomatic and thus escape the attention of medical geneticists. Animal models of AD provide a powerful resource for longitudinal and in-depth analyses, but traditionally are only studied on one genetic background. These limitations create a critical need for innovative approaches that take advantage of ‘high-risk’ FAD mutations in animal models in combination with genetic diversity in order to identify resilient genetic backgrounds that can be used to gain a better understanding of molecular mechanisms underlying resilience. To discover genetic modifiers of FAD, we generated a novel mouse panel of genetically diverse mice carrying FAD mutations in APP and PS1. Mice were phenotyped across the lifespan using construct valid cognitive and neuropathological assays, and genetic interval mapping was used to identify loci associated with resilience to cognitive decline and Aβ pathology. We observed wide variation in the age at onset and severity of AD symptoms in our FAD mouse population, which parallels variation observed in humans with high-risk FAD mutations. Results from our genetic interval mapping identified multiple genomic regions associated with resilience or susceptibility to AD, including the APOE locus and two novel quantitative trait loci. As our goal is to discover novel genes and molecular networks that govern human AD resilience, genes and molecular networks underlying resilience to AD in our mouse studies will be integrated with existing human genetic data to prioritize candidates with high translational relevance. High-priority genes associated with resilience to AD in human cohorts will be targeted via genome-editing in relevant mouse models for functional validation. Since clinical and pathological hallmarks of FAD parallel those of sporadic late-onset AD cases, we expect modifiers discovered in our mouse studies will broadly generalize to all forms of AD.