When mouse APOE was humanised solely at residue 61 (Thr61 to Arg61) its lipoprotein binding preference changed to ﻿very low density lipoproteins (VLDLs) (akin to human APOE4), resulting in cognitive deficits and increased susceptibility to cardiovascular disease, consistent with human APOE4-dependent clinical features. Here, APOE is linked to cardiovascular disorder.