The role of apolipoprotein E in Alzheimer's disease: pharmacogenomic target selection

The association of inheritance of different apolipoprotein E (APOE, gene; a poE, protein) alleles with the risk and rate of onset of Alzheimer's diseas e (AD) is now well established and widely confirmed. While there are now a collection of hypotheses concerning the specific relationship of APOE polym orphisms to various phenotypic manifestations of AD, no single compelling t heory has been tested and universally accepted. The only clear fact emergin g during the past 6 years is that differences in APOE genotype affect the a verage rate of disease onset as a predictable function of the inheritance o f this polymorphic gene. Methods now exist to enable experimental designs t o study the metabolic effects of inheriting different APOE alleles, address ing what differences that may be present for many years, perhaps over the e ntire lifetime, can lead to earlier or later manifestations of the disease and are therapeutically tractable. This review summarizes part of an experi mental approach to identify biological pathways influenced by the different APOE polymorphisms that are relevant to the pathogenesis of AD. (C) 2000 P ublished by Elsevier Science B.V.