PROJECT SUMMARY/ABSTRACT Neurodegenerative tauopathies are among the most common causes of dementia and parkinsonism in middle to late adult life. Diagnostic accuracy for tauopathies is reasonably good (over 75%) for some of these disorders, such as progressive supranuclear palsy (PSP), but poor (<50%) for others, such as corticobasal degeneration. Developing better biomarkers for these disorders would be useful for diagnosis, prognosis and future clinical trials. The genetic, cell modeling and immunoassays proposed by investigators in this CWOW address these important research objectives. The discovery of genetic variants that modulate risk and severity of tauopathy could provide significant insight into disease pathogenesis, as well as illuminate key pathways to target for potential therapeutics. Three genomic loci were reported in 2011 for the GWAS of PSP, including STX6, EIF2AK3, and MOBP, but the mechanisms by which each polymorphism impact disease risk remain unknown. Discovery of genetic factors that mediate sensitivity or resistance to tauopathy in Projects 1 and 2 will potentially necessitate development of novel resources to elucidate how each gene is functionally linked to tau deposition and toxicity in disease. Core C will generate new research tools to provide the Center with the means to uncover the underlying mechanisms for risk of disease mediated by the genetic variants, as well as identifying common pathways that potentially include multiple genetic modifiers and would thus represent ideal pathways to target therapeutically. In this Center, Core C plays an essential role through its large collection of pathologically-confirmed tauopathies and for provision of services to the research projects. In particular, we will provide biologic material from human tauopathy brains, as well as assist with the neuropathologic characterization and quantitation of tau burden in humans and mice. We will also validate the relationship between tau pathology and key discoveries by project investigators. Finally, we will establish novel assays to provide mechanistic insight into the link between genetic modifiers and disease.