The relationship between metabolic alterations induced by the consumption of a high-fat diet (HFD) and the risk of developing neurodegenerative diseases such as Alzheimer's disease (AD) has been extensively studied. In particular, the induction of neuronal insulin resistance, endoplasmic reticulum stress, and the production of reactive oxygen species by chronic exposure to high concentrations of saturated fatty acids (sFAs), such as palmitic acid (PA), have been proposed as the cellular and molecular mechanisms underlying cognitive decline. Lipid metabolism affects many processes critical for cellular homeostasis. However, questions remain as to whether neuronal exposure to high sFA levels contributes to the onset and progression of AD features, and how their metabolism plays a role in this process. Therefore, the aim of this work is to review the accumulated evidence for the potential mechanisms by which the neuronal metabolism of sFAs affects signaling pathways that may induce biochemical changes in the AD hallmark protein Tau, ultimately promoting its aggregation and the subsequent generation of neurofibrillary tangles. In particular, the data presented here provide evidence that PA-dependent metabolic stress results in an imbalance in the activities of protein kinases and deacetylases that potentially contribute to the post-translational modifications (PTMs) of Tau.