Distinct neuronal and glial tau pathologies define corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Additional Alzheimer disease, TDP-43, and Lewy body copathologies are also common. The interplay of these pathologies with clinical symptoms remains unclear as individuals can present with corticobasal syndrome, frontotemporal dementia, PSP, or atypical Parkinsonism and may have additional secondary impairments. We report clinical, pathological, and genetic interactions in a cohort of CBD and PSP cases. Neurofibrillary tangles and plaques were common. Apolipoprotein E (APOE)ε4 carriers had more plaques while PSP APOEε2 carriers had fewer plaques. TDP-43 copathology was present and age-associated in 14% of PSP, and age-independent in 33% of CBD. Lewy body copathology varied from 9% to 15% and was not age-associated. The primary FTD-Tau burden-a sum of the neuronal, astrocytic and oligodendrocytic tau-was not age-, APOE-, or MAPT-related. In PSP, FTD-Tau, independent of copathology, associated with executive, language, motor, and visuospatial impairments, while PSP with Parkinsonism had a lower FTD-Tau burden, but this was not the case in CBD. Taken together, our results indicate that the primary tauopathy burden is the strongest correlate of clinical PSP, while copathologies are principally determined by age and genetic risk factors.