The effect of ApoE genotype on grey matter (GM) atrophy was studied on a cohort of 750 healthy elderly volunteers (age range 63-75 years). High-resolution T1-weighted MR images were processed using both voxel-based morphometry and region of interest analysis for hippocampal volume estimation. Significant decrease of grey matter in epsilon(4) homozygous subjects (n = 12), as compared both to epsilon(4) heterozygous subjects (n = 175) and to noncarrier (n = 563) subjects, was found bilaterally in the medial temporal lobe, including the hippocampus, and extending over the superior temporal gyrus. By contrast, no significant difference was observed between epsilon(4) heterozygous subjects and noncarriers at the level of the medial temporal lobe. Follow-up of the cohort cognitive performances over 4 years after their MRI exam revealed that, as compared to noncarrier subjects, the relative risk of cognitive impairment was 5.9 for epsilon(4) homozygous subjects (P = 0.03), while it was not different from 1 for epsilon(4) heterozygous subjects (P = 0.92). These findings indicate that, in the age range of this cohort, ApoE-4 effects on cortical atrophy and cognitive performances of healthy elderly are limited to epsilon(4) homozygous subjects.