In the aging brain and especially in AD pathology, lipid metabolism, and in particular that of SM, undergoes significant changes. By using a shotgun lipidomics approach Han and colleagues have compared levels of over 800 lipid species in control and AD brains and demonstrated a significant decrease in SM and increases in ceramide levels in the affected brain. They suggested a model in which an AD-related increase in SMase activity results in faster SM hydrolysis (and increased ceramide production) which would lead to alterations in lipid raft formation (Han et al., 2011) . These authors also hypothesized that this would impair functions of GLUT4, which was previously shown to be functionally linked to lipid rafts (Michel and Bakovic, 2007) and lead to the dysfunctions in energy homeostasis characteristic of the disease. Moreover it was also shown that accumulation of the amyloid peptide in neuronal cells leads to SMase activation and SM depletion which, in turn, affects cellular trafficking and abnormal APP processing (Soreghan et al., 2003) . Further work demonstrated that the most toxic form of amyloid peptide Aβ 42 can also activate SMase (Grimm et al., 2005; Grosgen et al., 2010) . Since excessive SMasemediated cleavage of SM occurs early in AD it is likely to disrupt a range of protein-lipid interactions and hence downstream signaling pathways (Haughey et al., 2010) . In addition to AD-linked SMase over-activity, there have been reports of deficiencies of the enzymes responsible for sphingolipid synthesis (Piccinini et al., 2010) .