APOE-ε4 Shapes the Cerebral Organization in Cognitively Intact Individuals as Reflected by Structural Gray Matter Networks

Abstract

Gray matter networks (GMn) provide essential information on the intrinsic organization of the brain and appear to be disrupted in Alzheimer's disease (AD). Apolipoprotein E (APOE)-ε4 represents the major genetic risk factor for AD, yet the association between APOE-ε4 and GMn has remained unexplored. Here, we determine the impact of APOE-ε4 on GMn in a large sample of cognitively unimpaired individuals, which was enriched for the genetic risk of AD. We used independent component analysis to retrieve sources of structural covariance and analyzed APOE group differences within and between networks. Analyses were repeated in a subsample of amyloid-negative subjects. Compared with noncarriers and heterozygotes, APOE-ε4 homozygotes showed increased covariance in one network including primarily right-lateralized, parietal, inferior frontal, as well as inferior and middle temporal regions, which mirrored the formerly described AD-signature. This result was confirmed in a subsample of amyloid-negative individuals. APOE-ε4 carriers showed reduced covariance between two networks encompassing frontal and temporal regions, which constitute preferential target of amyloid deposition. Our data indicate that, in asymptomatic individuals, APOE-ε4 shapes the cerebral organization in a way that recapitulates focal morphometric alterations observed in AD patients, even in absence of amyloid pathology. This suggests that structural vulnerability in neuronal networks associated with APOE-ε4 may be an early event in AD pathogenesis, possibly upstream of amyloid deposition.

Keywords: APOE; Alzheimer’s disease; gray matter networks; independent component analysis; processing speed.

Figure 1

Structural GMn. (A) Surface rendering of four exemplary GMn identified in our sample with structural ICA. In each network, warm colors (red–yellow) indicate areas that are significantly related among each other in terms of GM volume. Cold colors (green–blue) denote the anticorrelation network, that is, brain regions that display a negative correlation with the areas in the positive correlation network. (B) Chord diagram illustrating the correlation matrix among all the 16 structural networks. Each sector along the circle, measured by arbitrary bin units in canvas coordinates, represents one structural network, with the length denoting the total amount of connections of each network. The thickness of inner ribbons indicates the strength of the correlation, while the sign is encoded by the color. (C) Volume rendering of the 16 structural components projected over axial slices, at their respective global maximum standardized coordinate.

Figure 2

APOE-ε4 homozygotes showed altered structural brain covariance. (A) Volume rendering of IC29 overlaid on the AD-signature composite region of interest, projected over sagittal slides. Brown areas indicate the spatial overlay between the two rendered volumes, which was evident in the inferior parietal, frontal as well as middle and inferior temporal areas and the precuneus. (B–D) Boxplot charts showing significantly heightened structural covariance of IC29 in APOE-ε4 homozygotes compared with both NC and heterozygotes. Τhe width of each box indicate the interquartile range, with the horizontal line showing the median. Data from each individual are shown in a separate vertical column. NC: noncarriers; ε4HET: APOE-ε4 heterozygotes; and ε4HMZ: APOE-ε4 homozygotes.

Figure 3

APOE-ε4 carriers display reduced connectivity between two pairs of structural networks. (A) Chord diagrams computed for each APOE subgroups highlighting the two network couplings (IC10/IC15 and IC02/IC17), which were affected by the APOE-ε4 genotype. The length of each outer sector is measured by arbitrary bin units in canvas coordinates and encodes the total amount of connections of a given network. The thickness inside each chord diagram encodes the strength of correlation. NC: noncarriers; ε4HET: APOE-ε4 heterozygotes; and ε4HMZ: APOE-ε4 homozygotes. (B) Surface rendering of the binarized IC10 and IC15, where an FDR-surviving significant effect of APOE-ε4 was found. (C) Group scatterplots with marginal densities reported aside each axes, showing the modulatory effect of APOE-ε4 on the linear association between two pairs of component. Shaded areas around the fitted regression lines indicated 90% confidence interval.