The apolipoprotein (apo) E4 isoform is the strongest risk factor for late-onset 
Alzheimer's disease (AD). ApoE4 is more susceptible to proteolysis than apoE2 
and apoE3 isoforms and carboxyl-terminal truncated apoE4 forms have been found 
in AD patients' brain. We have previously shown that a specific apoE4 fragment, 
apoE4-165, promotes amyloid-peptide beta 42 (Aβ42) accumulation in human 
neuroblastoma SK-N-SH cells and increased intracellular reactive oxygen species 
formation, two events considered to occur early in AD pathogenesis. Here, we 
show that these effects are allele-dependent and absolutely require the apoE4 
background. Furthermore, the exact length of the fragment is critical since 
longer or shorter length carboxyl-terminal truncated apoE4 forms do not elicit 
the same effects. Structural and thermodynamic analyses showed that apoE4-165 
has a compact structure, in contrast to other carboxyl-terminal truncated apoE4 
forms that are instead destabilized. Compared however to other allelic 
backgrounds, apoE4-165 is structurally distinct and less thermodynamically 
stable suggesting that the combination of a well-folded structure with 
structural plasticity is a unique characteristic of this fragment. Overall, our 
findings suggest that the ability of apoE fragments to promote Aβ42 
intraneuronal accumulation is specific for both the apoE4 isoform and the 
particular structural and thermodynamic properties of the fragment.