Abstract: AD, the main cause of dementia in elderly people, is a multifactorial neurodegenerative disorder characterized by a long prodromal phase (starting more than two decades before clinical symptoms appear) with brain accumulation/misfolding of amyloid β (Aβ) in insoluble amyloid plaques and of tau protein in neurofibrillary tangles. Even though the slow-progressing clinical development of the disease opens important diagnostic and therapeutic perspectives for the preventive medicine, there’s a general consensus that the amyloid deposition reaches early a plateau and does not change over time. On the contrary, the tau pathology is tightly linked with synaptic deterioration and neuronal death which eventually lead to the manifestation of classical symptomatology (Jack et al., 2018). Indeed, several lines of evidence support the notion that alterations of tau homeostasis actually drive the neurodegeneration in human tauopathies, including the most common AD where no genetic mutation in microtubule associated protein tau (MAPT) has been reported up to now. To this regard genetic, clinical and histopathological studies have undoutebly shown that abnormalities in tau protein(s) are sufficient to cause, both in vitro and in vivo, synaptic dysfunction, motor/sensorimotor and cognitive deficits indicative of loss of selective vulnerable neuronal populations (Spillantini and Goedert, 2013). Secondly, compelling evidence have also demonstrated that tau proteins have necessary, not-dispensable role in Aβ-dependent neurodegeneration, both in cellular and animal AD models and in elderly individuals (Iqbal and Gong, 2016). Moreover, both the “amyloid-cascade hypothesis” (i.e. Aβ is the initial insult driving tau pathology) and the “dual hit-model” (i.e. tau pathology is independent of Aβ which just provokes the tau spread to neocortex), which have been proposed to explain the etiopathogenesis of AD, posit a crucial place (i.e. induttive and/or permissive) of tau pathobiology in the chains of events ending in synaptic derangement and irreversible loss of neuronal viability (Small and Duff, 2008). Consistently, tau pathology correlates much more strongly than Aβ pathology with neurodegeneration and cognitive impairment, both spatially and temporally. In fact, the amyloid deposition does not cause the pronounced synaptic and neuronal loss which typically characterize the progressive clinical course of AD. Finally, tau is a common downstream effector both in Aβ-dependent and -independent pathogenic mechanisms such as increased amyloid precursor protein (APP) gene dosage/APP-derived-C-Terminal fragment (CTF,C99), cholesterol metabolism/endocytic, trafficking microglial immune activation, apoliprotein E allele epsilon 4.