Lipids participate in Amyloid Precursor Protein (APP) trafficking and processing - important
factors in the initiation of Alzheimer’s disease (AD) pathogenesis and influence the formation of neurotoxic
β-amyloid (Aβ) peptides. An important risk factor, the presence of ApoE4 protein in AD brain
cells binds the lipids to AD. In addition, lipid signaling pathways have a crucial role in the cellular
homeostasis and depend on specific protein-lipid interactions. The current review focuses on pathological
alterations of membrane lipids (cholesterol, glycerophospholipids, sphingolipids) and lipid metabolism
in AD and provides insight in the current understanding of biological membranes, their lipid structures
and functions, as well as their role as potential therapeutic targets. Novel methods for studying the
membrane structure and lipid composition will be reviewed in a broad sense whereas the use of lipid
biomarkers for early diagnosis of AD will be shortly summarized. Interactions of Aβ peptides with the
cell membrane and different subcellular organelles are reviewed. Next, the details of the most important
lipid signaling pathways, including the role of the plasma membrane as stress sensor and its therapeutic
applications are given. 4-hydroxy-2-nonenal may play a special role in the initiation of the pathogenesis
of AD and thus the “calpain-cathepsin hypothesis” of AD is highlighted. Finally, the most important
lipid dietary factors and their possible use and efficacy in the prevention of AD are discussed.