The inheritance of the apolipoprotein E (apoE) epsilon4 allele is a prevailing 
risk factor for sporadic and familial Alzheimer's disease (AD). ApoE isoforms 
bind directly to Alzheimer's amyloid beta (Abeta) peptides both in vitro and in 
vivo. Recent studies suggest that association of apoE with lipids may modulate 
its interaction with Abeta. We examined the binding of lipid-associated and 
delipidated apoE3 and apoE4 isoforms to Abeta utilizing a solid-phase binding 
assay and estimated the dissociation constants for the interaction of various 
apoE and Abeta species. Using native apoE isoforms from stably transfected RAW 
264 and human embryonic kidney 293 cells, apoE3 had greater affinity than apoE4 
for both Abeta1-40 and Abeta1-42. Delipidation of apoE decreased its affinity 
for Abeta peptides by 5-10-fold and abolished the isoform-specificity. 
Conversely, incorporation of apoE isoforms produced by baculovirus-infected Sf9 
cells into reconstituted human high-density-lipoprotein lipoparticles restored 
the affinity values for Abeta peptides and resulted in preferential binding of 
apoE3. The data demonstrate that native lipid-associated apoE3 binds to Abeta 
peptides with 2-3-fold higher affinity than lipid-associated apoE4. Since the 
isoforms' binding efficiency correlate inversely with the risk of developing 
late-onset AD, the results suggest a possible involvement of apoE3 in the 
clearance or routing out of Abeta from the central nervous system as one of the 
mechanisms underlying the pathology of the disease.