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Since the first clinical case reported more than 100 years ago, it has been a long and winding road to demystify the initial pathological events underling the onset of Alzheimer’s disease (AD). Fortunately, advanced imaging techniques extended the knowledge regarding AD origin, being well accepted that a decline in brain glucose metabolism occurs during the prodromal phases of AD and is aggravated with the progression of the disease. In this sense, in the last decades, the post-translational modification O -linked β- N -acetylglucosaminylation ( O -GlcNAcylation) has emerged as a potential causative link between hampered brain glucose metabolism and AD pathology. This is not surprising taking into account that this dynamic post-translational modification acts as a metabolic sensor that links glucose metabolism to normal neuronal functioning. Within this scenario, the present review aims to summarize the current understanding on the role of O -GlcNAcylation in neuronal physiology and AD pathology, emphasizing the close association of this post-translational modification with the emergence of AD-related hallmarks and its potential as a therapeutic target. [ABSTRACT FROM AUTHOR]