These discoveries led to propose the “cholinergic hypothesis of AD,” in which the lacks of acetylcholine was responsible for triggering AD pathology, therefore specific drugs were selected by their capacity to increase acetylcholine, including AChE and BuChE inhibitors or nAChR agonists (Bartus et al., 1982; Mangialasche et al., 2010). This evidence concerns the gene ACHE and Alzheimer disease.