Apolipoprotein-E4 (ApoE4) carriers show altered small-world properties in the default mode network of the brain

Abstract

Apolipoprotein-E (ApoE), specifically the e4 allele, has been identified as a risk factor for Alzheimer’s disease (AD). The prevalence of the gene in 25% to 30% of the population necessitates careful examination of its role in neuroregulation and its impact on distributed brain networks. In this study, large-scale and small-world anatomical cortical networks are assessed in cognitive normal (CN) subjects with differing apolipoprotein-E4 (ApoE4) gene expression. The large-scale anatomical networks are estimated from cortical thickness measurements derived from magnetic resonance imaging in 147 CN subjects examined in relation to the ApoE4 genotype (e4+ carriers (n = 41) versus e4− non-carriers (n = 106)). Brain networks were constructed by thresholding anatomical cortical thickness correlation matrices of 68 bilateral brain regions analyzed using well-established graph theoretical approaches. Compared to non-carriers, carriers showed increased interregional correlation coefficients in regions such as the precentral, superior frontal and inferior temporal lobes, and most of the altered connections were intra-hemispheric and limited primarily to the right hemisphere. The number of long-length anatomic connections in carriers (26.1%) was significantly higher compared to non-carriers (17.9%). Carriers showed a reduced amount of short connections in the frontal lobe as compared to non-carriers, but an increased presence of long-range connections was observed in the frontal lobe. Furthermore, ApoE4 carriers demonstrated abnormal small-world architecture in the cortical networks with increased clustering coefficient and path lengths as compared to non-carriers, suggesting a less optimal topological organization of their brain networks. Finally, as compared to non-carriers, ApoE4 carriers demonstrated higher betweenness in regions such as middle temporal, parahippocampal gyrus, posterior cingulate and insula of the default mode network, also seen in subjects with AD and mild cognitive impairment. The results suggest that the complex morphological cortical connectivity patterns are altered in ApoE4 carriers, providing evidence for disruption of integrity in large-scale anatomical brain networks in asymptomatic ApoE4 carriers.