In a sample of 1186 healthy subjects aged 65 to 89 years who were scanned twice with MRI 3.6 years apart, we studied the effects of age and ApoE-epsilon4 allele load on the rate of atrophy of grey matter and hippocampus. Rates of grey matter and hippocampal volumes loss were computed from T1-weighted magnetic resonance images using voxel-based morphometry and region of interest analysis. Longitudinal analysis showed that an age-related annual rate of grey matter volume loss was only seen in epsilon4 homozygotes only (n=14) whereas no age effect was seen epsilon4 heterozygotes (n=239) and in noncarriers (n=933). ApoE-epsilon4 homozygotes also had a significantly larger rate of hippocampal volume loss than heterozygotes or noncarriers. During the same period, no effect or interaction of ApoE genotype and age was observed on cognitive decline, as assessed by the Mini Mental State Examination (MMSE). These data do not suggest an epsilon4 gene dose effect on the rate of hippocampal volume loss in healthy elderly subjects as most of the effect was limited to homozygotes. Hippocampal volume loss may not be a good imaging marker to understand the effect of the ApoE-epsilon4 allele on the risk of dementia in a population-based setting. It could be hypothesized that the impact of a single ApoE-epsilon4 allele on brain structures is largely delayed in time.
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