Overview of Szutowicz et al. (Neurochem Res 2013) in this issue is focusing on specific features of acetyl-CoA metabolism in the cholinergic compartment of the brain. Authors are suggesting that deficit of that metabolite can act as a trigger for several cholinergic encephalopathies, with special emphasis on Alzheimer disease (AD). Central role of acetyl-CoA and its metabolic paths in neurodegeneration are charted starting from its synthesis in mitochondria, followed by utilization in energy metabolism, as well as transport into cytoplasm and participation in the synthesis and turnover of neurotransmitter acetylcholine to emergence of diseased states. Various putative pathogenic signals are evaluated that might be responsible for acetyl-CoA deficit ending up in development of neurodegeneration, unraveling exceptional susceptibility of cholinergic system. They are discussed in context of other existing alternative hypotheses on AD etiology. Overview is thoroughly documented (178 references) and is supported by results accomplished by extensive research in Prof. Szutowicz's laboratory (approximately 25 original papers).