Systems Genetics Analysis of Resilience to Tauopathy in ADRD

Project summary Tauopathy is a major component of Alzheimer's disease, frontotemporal dementia, and other Alzheimer's disease-related dementias. Compared to other proteinopathies, tauopathy most closely tracks with cognitive and non-cognitive symptoms of these diseases, hinting at a critical role in neurodegeneration. Individual differences in tau pathogenesis, as well as rate and distribution of progression, largely determine disease presentation. Interestingly, these differences appear to be genetically controlled. There are a number of challenges to identifying genetic modifiers of tauopathy in human populations (including relatively few individuals carrying causative tau mutations, the reality of prohibitively complex human genomes, and the likely contribution of many small-effect size variants). Therefore, a well-designed mouse genetic reference panel may be key to overcoming these challenges. Here, we propose to combine a well-characterized mouse model of tauopathy, the PS19 transgenic line (P301S MAPT mutation), with the genetically diverse BXD family of mice, to establish the FTD- BXD population of mice in order to interrogate genetic and molecular modifiers of tauopathy. The FTD-BXD mice will allow us to identify genetic factors that underlie resilience to tauopathy; such resilience factors may represent novel therapeutic targets to prevent, delay, or treat FTD and other tauopathy-dominant ADRDs.