Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: implications for the pathogenesis and treatment of Alzheimer disease.

The apolipoprotein E4 (APOE4) allele is associated with an early age of onset of the nonfamilial form of Alzheimer disease (AD) and with increased beta protein amyloid deposition in the brain. These two observations may both arise from an effect of the apoE family of proteins on the rate of in vivo amyloidogenesis. We report here that apoE3, the common apoE isoform, is an in vitro amyloid nucleation inhibitor at physiological concentrations. A significant delay in the onset of amyloid fibril formation by the beta-amyloid protein of AD (beta 1-40) was observed at a low apoE3 concentration (40 nM), corresponding to an apoE3/beta protein molar ratio of 1:1000. The inhibitory activity of a proteolytic fragment of apoE3, containing the N-terminal 191 amino acids, is comparable to the native protein, whereas the C-terminal fragment has no activity. ApoE4 is equipotent or slightly less potent than apoE3, which may be due to its inability to form a disulfide dimer, since the apoE3 dimer is a significantly more potent nucleation inhibitor than apoE4. Neither apoE3 nor apoE4 inhibits the seeded growth of amyloid or affects the solubility or structure of the amyloid fibrils, indicating that apoE is not a thermodynamic amyloid inhibitor. We propose that the linkage between the APOE4 allele and AD reflects the reduced ability of APOE4 homozygotes to suppress in vivo amyloid formation.