Evidence that caspase-6 activation is associated with a protracted type of cell death in serum-deprived human primary neurons [
42] and renders neurons susceptible to oxidative stress, resulting in either immediate or delayed apoptosis [
43], as opposed to the other effector caspases that instead lead to rapid induction of apoptosis. These unique characteristics of caspase-6, less studied than caspase-3, have drawn attention to its potential importance. Caspase-6 in inactivated form is ubiquitous in the human fetal brain and peripheral tissues showing its importance for fetal development [
44]. In normal conditions, the human adult brain expresses low levels of caspase 6. However, neuronal activation of caspase-6 is an early event in AD and correlates with adverse clinical outcomes. Increased caspase-6 activity in the anterior olfactory nucleus reflected the degeneration in the entorhinal cortex (affected in Braak stage 1) and correlated with tau pathology in human AD olfactory bulb brain Sect. [
45]. Also, in aged non-cognitively impaired individuals, the level of caspase-6 in the entorhinal cortex and CA1 negatively correlates with cognitive domains initially affected in AD [
46]. In a study probing the locus coeruleus and dorsal raphe nucleus, brain regions among the first to develop AD-tau pathology, levels of caspase-6 activation in neurons associated with increased Braak staging and burden of neurofibrillary tangles positive for phospho-tau [
47]. Levels of caspase-6-cleaved tau are inversely correlated with global cognitive scores in non-demented individuals, supporting tau that cleavage by active caspase-6 may be an early event in AD pathophysiology [
21,
48,
49]. In addition to Asp421, caspase-6 cleaves tau at other sites, including Asp402 and Asp13 [
23,
32] (Fig.
2). Caspase-6 is particularly efficient in cleaving tau at Asp13 [
50]. Caspase-6-cleavage of tau at Asp13 generates two fragments [
32]: 1–13 with unknown function and 14–441 with a role in tangle maturation [
51,
52]. Caspase-6- cleavage of tau at Asp402 generates a 1-402 fragment, associated with neurodegeneration, and the 403–441 with unknown functions [
52]. Altogether, both active caspase-6 and tau truncated at Asp402 and Asp13 are present in neurofibrillary tangles, neuritic plaques, and neuropil threads in sporadic and familial AD but absent in brains without AD pathology [
7,
23,
48,
53].
Despite confluent evidence of the role of caspase-6 activation and caspase-6-cleaved in AD pathogenesis [
48,
54], only recently monoclonal antibodies against these tau specimens became available to directly investigate the frequency of tau D13 and D402 in tauopathies. Theofilas et al. [
7] probed postmortem human brain tissue with a recently developed 5-plex immunohistochemistry with monoclonal novel neoepitope monoclonal antibody against caspase-6 cleaved tau (D402 and D13). The use of multiplex immunostaining allowed these researchers to detect that the number of neurons positive for caspase-6 cleaved tau and phospho-tau in AD is equivalent. However, the overlapping is only 45%. It suggests that currently used antibodies do not flag a significant portion of neurons with tau pathology to label pathological tau in postmortem studies and fluid-based biomarkers based on phospho-tau.