Tau truncation by active caspase-6 facilitates tau pathogenesis by producing toxic fragments prone to self-aggregation. We previously demonstrated that neuronal active caspase-6 co-occurs with phosphorylated tau (p-tau) during the earliest stages of Alzheimer's disease (AD) and that the percentage of neurons positive for both active caspase-6 and p-tau increases as the disease progresses. Although caspase-6-mediated cleavage of tau appears to be a key contributor to tau pathology, questions concerning the relationship between caspase-6 activation, tau cleavage, and the formation of p-tau aggregates remain. We developed novel neoepitope antibodies against tau truncated by caspase-6, performed 5-plex immunofluorescence on tissue microarrays-sampled from the middle frontal gyrus (MFG) and the inferior temporal gyrus (ITG)-and quantified neuronal and glial positivity for active caspase-6, tau truncated at D402 and D13 (tr-tau; C- and N-terminal, respectively), and tau phosphorylated at Ser202 (p-tau; CP13) in AD, argyrophilic grain disease (AGD), corticobasal degeneration (CBD), Pick's disease (PiD), progressive supranuclear palsy (PSP), and healthy aging controls. Percentages of neurons positive for p-tau were as to be expected in all 17 cases. AD showed the highest burden of neuronal positivity for active caspase-6, followed by PiD (Figure 1, Table 1). Mean percentages of neurons positive for D402 and D13 were markedly higher (1.80 to 236x) in AD and PiD relative to the 4-repeat tauopathies tested (Figure 1, Table 1). Surprisingly, in AD, only ∼44.36% of these neurons showed p-tau positivity (Figure 2). Regarding glial positivity, active caspase-6 and tr-tau were present in PSP but scarce in CBD (Figure 3, Table 2). (1) Caspase-6 activation and cleavage of tau is more prominent in AD and, to a lesser extent, PiD. Caspase-6 modulation could be a promising therapeutic for AD, and possibly PiD, but not 4-repeat tauopathies. (2) In AD, there is a substantial number of neurons with tr-tau inclusions that lack p-tau, which suggests that biofluid biomarkers of tr-tau (specifically at N-terminal sites) would allow for better detection of AD and differentiation of AD from 4-repeat tauopathies.