The overarching goal of our clinical research is to use a neuropathological approach (human tissue based) to identify changes in the brain that can be correlated with clinical, genetic, transcriptomic and other measures to identify mechanisms contributing to neurodegenerative tauopathies, a group of related disorders including Alzheimer’s. The clinical laboratory is rooted in “classical” neuropathology, a methodical albeit laborious approach involving extensive clinical case reviews alongside manual examination of brain tissues under the microscope, often with the same methods that the founders of the field used, such as the silver stains pioneered by Alois Alzheimer over 100 years ago. Careful microscopic observation is remarkably powerful when correlated with clinical symptomatology, and has enabled us to define new diagnostic categories and staging systems, including the first description of primary age-related tauopathy. We have been deeply involved with efforts to define criteria for other tauopathies, including chronic traumatic encephalopathy, aging-related tau astrogliopathy, and progressive supranuclear palsy. These studies have been done in a highly collaborative spirit, leveraging a large international network of neuropathologists working closely together, sharing tissues and ideas. These projects, which depend, on input and knowledge from many investigators, have reinforced our respect for the collective wisdom of the neuropathology clinical research community and how it forms the foundation for transformational conceptual innovation. Well-characterized human tissues, imbued with the knowledge of expert pathologists, combined with cutting edge technological innovations is a potent force for discovery - a strategy we use to uncover novel associations and candidate disease mechanisms. Our genetic studies, transcriptomic studies, stem cell models, and now computer vision/deep learning models have been our springboard to launch off the foundation we built using classical neuropathology. New emerging unpublished work from our team highlights innate immunity and oligodendrocyte dysfunction in tauopathy. Once again, these projects are highly collaborative: we work closely with the Tau Consortium, the Progressive Supranuclear Palsy (PSP) genetics consortium, and a group that we founded, the primary age-related tauopathy working group.