Apolipoprotein E4 (apoE4) is a major risk factor for Alzheimer's disease (AD). Several hypotheses have been proposed to explain the association of the APOE epsilon4 allele with AD; however, the mechanisms underlying this association are largely unknown. Initially, apoE was thought to be synthesized primarily by astrocytes but not by neurons in the brain. However, subsequent studies have demonstrated that central nervous system neurons also express apoE under diverse physiological and pathological conditions. Detailed studies of the structure and biophysical properties of apoE isoforms have demonstrated unique properties distinguishing apoE4 from apoE3. Because the structural and biophysical properties of a protein determine how it functions under normal and abnormal conditions, apoE4, with its multiple cellular origins and multiple structural and biophysical properties, might contribute to the pathology of AD through several different mechanisms. Some of these mechanisms might be suitable targets for the development of new treatments for AD.

Copyright 2004 Humana Press Inc.