This FOA encouarges multidisciplinary and interdisciplinary research to elucidate how Apolipoprotein E, lipoprotein receptors and CNS lipid homeostasis influence brain aging and the transition to neurodegeneration in Alzheimers disease (AD). The ultimate goal is to gain an in depth understanding of the mechanisms by which the Apolipoprotein E e4 allele confers increased AD risk for the purpose of advancing the overall search for efficacious AD treatments and Apolipoprotein E e4-directed therapeutics in particular. To this end we encourage research spanning multiple levels of analysis in multiple species (from mice to man). Studies aimed at identifying new therapeutic targets for the treatment of AD and other age-related neurodegenerative conditions associated with lipid neurobiology are strongly encouraged. Also of great interest are projects that aim to use lipidomics, various types of imaging and other cutting edge technologies to identify and develop early biomarkers of neurodegeneration associated lipid dyshomeostasis.