The amyloid hypothesis of Alzhemer\'s disease (AD) postulates that the generation of amyloid-beta (Aβ) peptide from the amyloid precursor protein (APP) by the action of the γ-secretase complex is one of the principal causes of AD. This idea is supported by the identification of several hereditary mutations in the APP gene or in the PSEN1 and PSEN2 genes that encode Presenilin-1 and Presenilin-2, the catalytic component of the γ-secretase complex. The assumption at that time was that familial AD (FAD), mutations lead to a gain of function phenotype, increasing the ratio between the levels of the toxic Aβ1–42, and the less toxic Aβ1–40 peptide (Kuperstein et al., 2010). Actually, the ratio Aβ1–42/Aβ1–40 is the principal cause of the toxic effect as some FAD mutations in APP decrease the levels of Aβ1–40 without changing the total levels of Aβ1–42 (Ancolio et al., 1997). Pharmaceutical companies started the race to design new highly specific γ-secretase inhibitors (GSIs) with good pharmacological properties to jump into the clinic. The reduction of the circulating levels of Aβ1–42 in AD mouse models rapidly supported this approximation, and one of the lead compounds, Semagacestat (Lilly), entered the phase Ⅲ clinical trials. However, results were not as good as initially expected, and the appearance of several skin cancer problems and a reduction, rather than an improvement, in the cognitive performance of the patients lead the FDA to stop the clinical trials.