There are three major apolipoprotein E (apoE) isoforms. Although APOE-epsilon3 
is considered a longevity gene, APOE-epsilon4 is a dual risk factor to 
atherosclerosis and Alzheimer disease. We have expressed full-length and N- and 
C-terminal truncated apoE3 and apoE4 tailored to eliminate helix and domain 
interactions to unveil structural and functional disturbances. The N-terminal 
truncated apoE4-(72-299) and C-terminal truncated apoE4-(1-231) showed more 
complicated or aggregated species than those of the corresponding apoE3 
counterparts. This isoformic structural variation did not exist in the presence 
of dihexanoylphosphatidylcholine. The C-terminal truncated apoE-(1-191) and 
apoE-(1-231) proteins greatly lost lipid binding ability as illustrated by the 
dimyristoylphosphatidylcholine turbidity clearance. The low density lipoprotein 
(LDL) receptor binding ability, determined by a competition binding assay of 
3H-LDL to the LDL receptor of HepG2 cells, showed that apoE4 proteins with 
N-terminal (apoE4-(72-299)), C-terminal (apoE4-(1-231)), or complete C-terminal 
truncation (apoE4-(1-191)) maintained greater receptor binding abilities than 
their apoE3 counterparts. The cholesterol-lowering abilities of apoE3-(72-299) 
and apoE3-(1-231) in apoE-deficient mice were decreased significantly. The 
structural preference of apoE4 to remain functional in solution may explain the 
enhanced opportunity of apoE4 isoform to display its pathophysiologic functions 
in atherosclerosis and Alzheimer disease.