Human apolipoprotein E (apoE) exists as three common isoforms that differ by single amino acid substitutions. ApoE4 (112R/158R) is the single strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD), which is the fastest growing cause of death in the ageing population of Australia. At the protein level, previous studies suggest that the conformational landscape of apoE4 is different to that of the wild-type apoE3 (112C/158R). However, the exact conformational characteristics linking apoE4 to LOAD has not yet been defined due to a lack of high resolution structural information. This study aims to (1) express and purify human apoE3 & apoE4; (2) determine and compare the crystal structure of apoE isoforms; and (3) elucidate the nature of the disease-associated conformational landscape. Recombinant apoE isoforms have been expressed in E. coli and purified using standard liquid chromatography procedures to yield milligram quantities of highly pure protein. Crystallisation trials under biologically-relevant conditions are underway. Preliminary molecular dynamics (MD) simulations have also been performed that demonstrate subtle, yet significant points of difference in the dynamics of apoE3 and apoE4. This study will provide critical structural information that will afford insight into defining the link between apoE4 and age-related dementia.