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. 2012 Jun 13;32(24):8254-62.
doi: 10.1523/JNEUROSCI.0305-12.2012.

Gender modulates the APOE ε4 effect in healthy older adults: convergent evidence from functional brain connectivity and spinal fluid tau levels

Jessica S Damoiseaux  1 , William W Seeley, Juan Zhou, William R Shirer, Giovanni Coppola, Anna Karydas, Howard J Rosen, Bruce L Miller, Joel H Kramer, Michael D Greicius; Alzheimer's Disease Neuroimaging Initiative
Collaborators, Affiliations

Gender modulates the APOE ε4 effect in healthy older adults: convergent evidence from functional brain connectivity and spinal fluid tau levels

Jessica S Damoiseaux et al. J Neurosci. .

Abstract

We examined whether the effect of the apolipoprotein E (APOE) genotype on functional brain connectivity is modulated by gender in healthy older human adults. Our results confirm significantly decreased connectivity in the default mode network in healthy older APOE ε4 carriers compared with ε3 homozygotes. More important, further testing revealed a significant interaction between APOE genotype and gender in the precuneus, a major default mode hub. Female ε4 carriers showed significantly reduced default mode connectivity compared with either female ε3 homozygotes or male ε4 carriers, whereas male ε4 carriers differed minimally from male ε3 homozygotes. An additional analysis in an independent sample of healthy elderly using an independent marker of Alzheimer's disease, i.e., spinal fluid levels of tau, provided corresponding evidence for this gender-by-APOE interaction. Together, these results converge with previous work showing a higher prevalence of the ε4 allele among women with Alzheimer's disease and, critically, demonstrate that this interaction between APOE genotype and gender is detectable in the preclinical period.

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Figures

Figure 1.
Figure 1.
Spatial maps of the networks of interest and the control network. A–D, The group independent components selected for between-group statistics include three networks of interest—anterior (A), posterior (B), and ventral DMN (C)—and the primary visual network as a control (D). All are shown here using a posterior probability threshold of p > 0.5; MNI coordinates (in millimeters; numbers at the top) of the axial, sagittal, and coronal slices. Images are displayed in neurological convention.
Figure 2.
Figure 2.
APOE ε4 reduces default mode connectivity in healthy older adults. A, B, Functional connectivity is decreased in ε4 carriers compared with ε3 homozygotes in both the anterior (A) and the posterior (B) DMN. Bar graphs depict the distribution of the effects across subgroups. They show the mean parameter estimates of a selected region within the anterior DMN (right anterior cingulate gyrus) and the left posterior cingulate cluster within the posterior DMN for male and female ε3 homozygotes and male and female ε4 carriers. The difference across both genotype (p < 0.001) and gender (p = 0.005) is significant for the anterior cingulate gyrus. For the posterior cingulate gyrus, only the difference across genotype is significant (p = 0.001). The statistical maps, thresholded using TFCE and p < 0.05 familywise error corrected, are overlaid on the MNI152 brain; MNI coordinates (in millimeters) of the slices are displayed. Images are displayed in neurological convention.
Figure 3.
Figure 3.
Gender modulates the APOE effect on default mode connectivity. An APOE genotype-by-gender interaction was found in a precuneus/cuneus region within the posterior DMN. The bar graph shows the mean parameter estimates of this cluster, for male and female ε3 homozygotes and male and female ε4 carriers. The greatest reduction in functional connectivity was observed in the female ε4 carriers. The statistical maps, thresholded using TFCE and p < 0.01 uncorrected, are overlaid on the MNI152 brain; MNI coordinates (in millimeters) of the slices are displayed. Images are displayed in neurological convention.
Figure 4.
Figure 4.
The APOE effect on functional connectivity is most prominent in female ε4 carriers. A–C, Post hoc tests were performed for the posterior DMN for three contrasts: female ε3 homozygotes > female ε4 carriers (A), which showed a decrease in functional connectivity in female ε4 carriers, mainly in a large (>2000 voxel) cluster encompassing the cuneal cortex, precuneus, and posterior cingulate gyrus; male ε3 homozygotes > male ε4 carriers (B), which showed decreased posterior default mode connectivity in male ε4 carriers in a small (16 voxel) cluster in the left superior parietal cortex; and male ε4 carriers > female ε4 carriers (C), which showed small clusters of reduced functional connectivity in female ε4 carriers. The statistical maps, thresholded using TFCE and p < 0.01 uncorrected, are overlaid on the MNI152 brain; MNI coordinates (in millimeters) of the slices are displayed. Images are displayed in neurological convention.
Figure 5.
Figure 5.
CSF total tau levels provide convergent evidence for the modulation of the APOE effect by gender. The bar graph shows the significant APOE genotype-by-gender interaction observed for CSF total tau levels (p = 0.024), in the healthy older controls of the ADNI dataset. Healthy female ε4 carriers showed the highest mean total tau level. Post hoc testing revealed a significant difference between female ε4 carriers and female ε3 homozygotes (p = 0.046).
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