Recently, biochemical criteria were proposed to complement histological criteria for the diagnosis of dementia lacking distinctive histopathology (DLDH), the most common pathological variant of frontotemporal dementias (FTDs), based on evidence of a selective reduction of soluble tau proteins in brains from a large cohort of sporadic DLDH and hereditary FTD (HDDD2 family) patients. To ensure that these findings are not unique to the populations included in the initial report, we extended the previous work by analyzing 22 additional DLDH brains from the United States and international centers. Our biochemical analyses here confirmed the previous findings by demonstrating substantial reductions in soluble brain tau in gray and white matter of 14 cases and moderate reductions in 6 cases of DLDH. We also analyzed brain samples from an additional affected HDDD2 family member, and remarkably, unlike other previously studied members of this kindred, this patient's brain contained substantial amounts of pathological or insoluble tau. These findings confirm and extend the definition of DLDH as a sporadic or familial "tau-less" tauopathy with reduced levels of soluble brain tau and no insoluble tau or fibrillary tau inclusions, and the data also underline the phenotypic heterogeneity of HDDD2, which parallels the phenotypic heterogeneity of other hereditary neurodegenerative FTD tauopathies caused by tau gene mutations.