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INTRODUCTION Neurocognitive Disorder due to Alzheimer’s Disease: A Brief Overview According to DSM5, the term neurocognitive disorder (NCD) emphasizes that the cause of mental deficit lies in a pathology affecting neuronal circuits. The early clinical stages of NCD (mild-NCD/ MCI) are characterized by functional preservation of everyday activities. Instead, if the disorder has a functional impact it is defined as major-NCD (dementia). On the other hand, the definition of the underlying pathology allows for the etiological classification of NCD (American Psychiatric Association, 2013; Sachdev et al., 2015). Based on the pathological deposition of proteins in brain tissue, NCD due to AD is characterized by a dual proteinopathy in which neurodegeneration is associated with the deposition of amyloid and phosphorylated TAU protein (pTAU). AD is the main age-related degenerative NCD progressively involving memory, complex attention, executive functions, language, and visual-perceptual functions. Personality and behavioural changes are also frequent further complicating the clinical course. On the other hand, due to the late involvement of the movement centers, motor function is usually spared until the most advanced stages of the disease. The AD syndromic evolution reflects the progressive spread of pTAU pathology from the allocortex (entorhinal cortex and hippocampus) to the neocortex (Elahi and Miller, 2017; Hanseeuw et al., 2019). Observing the neuropathology of AD is the starting point for deciphering its pathophysiological mechanisms and, therefore, identifying the biomarkers of the disease and the possible therapeutic targets. The macroscopic pathological feature characterizing advanced AD is diffuse brain atrophy due to widespread neurodegeneration causing synaptic and neuronal loss. Actually, the disease begins decades earlier with amyloid accumulation in the neocortex but amyloid deposition, which is very common even in physiological aging, is not sufficient to cause AD. The fundamental question is: what triggers neurodegeneration? Probably, the excess of amyloid-beta (Aβ) induces neurodegeneration through toxic oligomers. Indeed, soluble Aβ oligomers cause a synaptic reduction with a decrease in long-term potentiation and memory. Moreover, oligomers can reduce blood flow in brain capillaries and induce hyperphosphorylation of the AD-relevant epitopes of TAU protein (Selkoe and Hardy 2016; Nortley et al., 2019). Thus, Aβ load triggers neurodegeneration through oligomers which induce unbalanced activation of neuronal kinases resulting in excessive production of pTAU that, in turn, aggregates in pTAU toxic oligomers and spreads from its initial location in allocortex to neocortex. Together, oligomeric Aβ, synaptic pTAU aggregates and glial inflammatory activation are the main neurotoxic factors involved in the manifestation of a clinically relevant neurocognitive disorder (Perez-Nievas et al., 2013; Jack et al., 2018a). Typically, AD pathology shows extracellular accumulation of Aβ peptides (Aβ or senile plaques), as well as the hyperphosphorylated tau protein aggregates inside the dying neurons named Edited by: Francisco Ciruela, University of Barcelona, Spain