Alzheimer’s disease risk and the isoform dependence of phospholipid-apolipoprotein E interaction

The ε4 allele of the APOE gene, encoding the E4 isoform of apolipoprotein E, is the leading genetic risk factor for late-onset Alzheimer’s disease. While many potential mechanisms have been proposed to explain this risk, no dominant or unifying process has yet emerged. Here, we explore the primary function of apolipoprotein E in lipid transport and metabolism, by examining its lipid association properties, to establish whether they show isoform dependence and thereby could mediate Alzheimer’s risk. We focus on ethanolamine plasmalogen, a phospholipid subclass known to be depleted in Alzheimer’s disease brain.