Dissecting the gene dose-effects of the APOE ε4 and ε2 alleles on hippocampal volumes in aging and Alzheimer's disease.

To investigate whether there is a specific dose-dependent effect of the Apolipoprotein E (APOE) ε4 and ε2 alleles on hippocampal volume, across the cognitive spectrum, from normal aging to Alzheimer's Disease (AD).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 ε4 and ε2 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.There was a dose-dependent effect of the ε4 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 ε2 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 ε2 alleles (Cohen's d = 0.23).Though no effect of ε4 was seen in CN subjects, our findings confirm and extend prior data on the opposing effects of the APOE ε4 and ε2 alleles on hippocampal morphology across the spectrum of cognitive aging

Freesurfer hippocampal region of interest.

<p>Coronal, sagittal, and axial (1.5T) T1-weighted MR images from the Freesurfer Image Analysis Suite of sample subject “Bert”, with color overlays depicting the extent of the Freesurfer hippocampal region of interest used to derive hippocampal volumes.</p

Demographics and Cognitive Summary by ε2.

<p>All means are reported ± 1 standard error. All <b>bolded</b> parameters were significant according to ANOVA, Chi-square analysis, or Fisher’s Exact Test as appropriate. CN = cognitively normal, MCI = mild cognitive Impairment, AD = Alzheimer’s Disease, ε2 = APOE epsilon 2.</p

Summary of effects for variables on hippocampal volume: <i>APOE</i> dose-dependent model.

<p>n = 662.</p><p>Results for model which treats APOE epsilon “X” allele effects as dose-dependent effects. APOE effect sizes of each variable are reported in terms of mm³/(unit variable), e.g., the effect of “Age” on the outcome variable, hippocampal volume, is −23.31 mm³/year of age. “:” denotes interaction terms between variables. Reference for the model is an APOE ε3/ε3 CN individual. Note the lack of a main effect of APOE epsilon 4 (“ApoE4”) in the model and thus in CN subjects.</p

Summary of unadjusted hippocampal volumes by <i>APOE</i> ε2 allele dose and diagnostic category.

<p>Unadjusted values. “ε2 dose” = copy number of APOE ε2 allele,</p><p>“SD” = standard deviation, “SE” = standard error of the mean. “Mean” units are mm³.</p

Summary of unadjusted hippocampal volumes by <i>APOE</i> ε4 allele dose and diagnostic category.

<p>Unadjusted values. “ε4 dose” = copy number of APOE ε4 allele,</p><p>“SD” = standard deviation, “SE” = standard error of the mean. “Mean” units are mm³.</p

Breakdown of subjects by diagnosis and <i>APOE</i> epsilon 4 status.

<p>CN = cognitively normal, MCI = mild cognitive Impairment, AD = Alzheimer’s Disease, ε4 = APOE epsilon 4.</p

Demographic and cognitive summary by ε4.

<p>All means are reported ± 1 standard error. All <b>bolded</b> parameters were significant according to ANOVA, Chi-square analysis, or Fisher’s Exact Test as appropriate. CN = cognitively normal, MCI = mild cognitive Impairment, AD = Alzheimer’s Disease, ε4 = APOE epsilon 4.</p

Summary of effects for variables on hippocampal volume: <i>APOE</i> nominal model.

<p>n = 660; n = 2 APOE ε2 CN homozygotes excluded. Results for model which treats APOE epsilon “X” allele effects as categorical or “carrier-status” effect. APOE effect sizes of each variable are reported in terms of mm³/(unit variable). “APOEX1” denotes the effect of 1 copy of APOEX, “APOEX2” denotes the effect of 2 copies of APOEX. Unlike the results of the above model, this model does not have the assumption of dose-dependency.</p><p>“:” denotes interaction terms between variables. Reference for the model is an APOE ε3/ε3 CN individual.</p

Dose-response of hippocampal volumes.

<p>Dose-dependency of hippocampal volume by <i>APOE</i> epsilon 4 allele load in Mild Cognitive Impairment (MCI) and Alzheimer Disease (AD). Each error bar is constructed using ±1 standard error of the mean.</p