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Advances in our understanding of the significance of regional and cellular (i.e., neuronal v. glial) differences in tangles with has improved our ability to differentiate Alzheimer disease (AD) from primary age-related tauopathy (PART), chronic traumatic encephalopathy (CTE), age-related tauopathy of astroglia (ARTAG), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and other tauopathies (1, 3, 15). This knowledge provides a novel platform for molecular and genetic studies. It has been known for nearly two decades that tauopathies are associated with MAPT, but we still do not understand why it manifests as different phenotypes. Surprisingly, Parkinson disease (PD) also has a strong association with H1, but generally minimal tauopathic burden. The odds ratio for these associations vary considerably, with ~5 for PSP, CBD and PART, but 1.5 for AD and PD. Is this because there are different risk alleles that underlie these associations in the context of different diseases or a single mechanism? This question is increasingly important as new clinical trials for primary tauopathies become an NIH focus. The contribution of this proposal will be to translate our expanding knowledge of tauopathy phenotypes to better understand the nature of the genetic risk associated with the H1 haplotype. This contribution will be significant because it will provide a foundation for further mechanistic studies that will elucidate the drivers of disease and pave the way for future clinical studies. This subcontract is essential because of the unique expertise from Dr. Jane Wu's team in studying tauopathies at molecular and cellular levels and in understanding the pathogenetic mechanisms of AD.