The present invention provides isolated apolipoprotein E (apoE) stable folding intermediates. The invention further provides methods for identifying compounds that alter the structure or level or activity of an apoE stable folding intermediate, as well as methods of inhibiting the formation or activity of stable folding intermediates of apoE. The invention further provides methods for reducing the level and/or activity of an apoE stable folding intermediate, and methods for treating disorders relating to apoE4 in a subject.