Dissecting the Gene Dose-Effects of the APOE ε4 and ε2 Alleles on Hippocampal Volumes in Aging and Alzheimer's Disease

Objective: To investigate whether there is a specific dose-dependent effect of the Apolipoprotein E (APOE) epsilon 4 and epsilon 2 alleles on hippocampal volume, across the cognitive spectrum, from normal aging to Alzheimer's Disease (AD). Materials and Methods: We analyzed MR and genetic data on 662 patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database-198 cognitively normal controls (CN), 321 mild-cognitive impairment (MCI) subjects, and 143 AD subjects-looking for dose-dependent effects of the epsilon 4 and epsilon 2 alleles on hippocampal volumes. Volumes were measured using a fully-automated algorithm applied to high resolution T1-weighted MR images. Statistical analysis consisted of a multivariate regression with repeated-measures model. Results: There was a dose-dependent effect of the epsilon 4 allele on hippocampal volume in AD (p = 0.04) and MCI (p = 0.02)-in both cases, each allele accounted for loss of >150 mm(3) (approximately 4%) of hippocampal volume below the mean volume for AD and MCI subjects with no such alleles (Cohen's d = -0.16 and -0.19 for AD and MCI, respectively). There was also a dose-dependent, main effect of the epsilon 2 allele (p<0.0001), suggestive of a moderate protective effect on hippocampal volume-an approximately 20% per allele volume increase as compared to CN with no epsilon 2 alleles (Cohen's d = 0.23). Conclusion: Though no effect of epsilon 4 was seen in CN subjects, our findings confirm and extend prior data on the opposing effects of the APOE epsilon 4 and epsilon 2 alleles on hippocampal morphology across the spectrum of cognitive aging.