Here, we report a large-scale digital histopathological study in a well-characterized autopsy cohort of bvFTD and PPA patients to address this knowledge gap and test the following hypotheses: (1) there is greater WM pathologic burden across regions in FTLD-Tau subtypes compared to subtypes of FTLD-TDP; (2) WM pathology burden is related to greater WM degeneration in FTLD-Tau compared to FTLD-TDP; and (3) there are distinct regional patterns of WM and GM pathology in FTLD-Tau and FTLD-TDP proteinopathies and their subtypes, which are in part related to clinical phenotype. Here, MAPT is linked to proteostasis deficiencies.