Disrupted topology of the resting state structural connectome in middle-aged APOE ε4 carriers

Abstract

The apolipoprotein E (APOE) ε4 allele is the best characterized genetic risk factor for Alzheimer's disease to date. Older APOE ε4 carriers (aged 60 + years) are known to have disrupted structural and functional connectivity, but less is known about APOE-associated network integrity in middle age. The goal of this study was to characterize APOE-related differences in network topology in middle age, as disentangling the early effects of healthy versus pathological aging may aid early detection of Alzheimer's disease and inform treatments. We performed resting state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) in healthy, cognitively normal, middle-aged adults (age 40-60; N = 76, 38 APOE ε4 carriers). Graph theoretical analysis was used to calculate local and global efficiency of 1) a whole brain rs-fMRI network; 2) a whole brain DTI network; and 3) the resting state structural connectome (rsSC), an integrated functional-structural network derived using functional-by-structural hierarchical (FSH) mapping. Our results indicated no APOE ε4-associated differences in network topology of the rs-fMRI or DTI networks alone. However, ε4 carriers had significantly lower global and local efficiency of the integrated rsSC compared to non-carriers. Furthermore, ε4 carriers were less resilient to targeted node failure of the rsSC, which mimics the neuropathological process of Alzheimer's disease. Collectively, these findings suggest that integrating multiple neuroimaging modalities and employing graph theoretical analysis may reveal network-level vulnerabilities that may serve as biomarkers of age-related cognitive decline in middle age, decades before the onset of overt cognitive impairment.

Keywords: APOE; Alzheimer's disease; Functional connectivity; Middle age; Network.

Figure 1.. Functional-by-structural hierarchical (FSH) mapping processing pipeline.

Figure 2.. Associations between APOE genotype and whole-brain functional and structural connectivity.

APOE ε4 carriers did not differ from non-ε4 carriers in the global or local efficiency of </p>(A) the rs-fMRI-derived whole brain functional network or </p>(B) the DTI-derived whole brain structural network. </p>(C) ε4 carriers had significantly lower global and local efficiency of the rsSC compared to non-ε4 carriers. ** p < .01.

Figure 3.. Associations between APOE genotype and resting state structural connectome (rsSC) resilience to node failure.

(A) APOE ε4 carriers did not differ from non-ε4 carriers in resilience when nodes were removed from the rsSC at random. </p>(B) When nodes were removed in order of “hubness,” ε4 carriers were initially resilient but soon showed lower resilience as progressively more central nodes were removed. * denotes group differences, p < .05.