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

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.

Cognitive correlates of spatial navigation: Associations between executive functioning and the virtual Morris Water Task.

Although effective spatial navigation requires memory for objects and locations, navigating a novel environment may also require considerable executive resources. The present study investigated associations between performance on the virtual Morris Water Task (vMWT), an analog version of a nonhuman spatial navigation task, and neuropsychological tests of executive functioning and spatial performance in 75 healthy young adults. More effective vMWT performance (e.g., lower latency and distance to reach hidden platform, greater distance in goal quadrant on a probe trial, fewer path intersections) was associated with better verbal fluency, set switching, response inhibition, and ability to mentally rotate objects. Findings also support a male advantage in spatial navigation, with sex moderating several associations between vMWT performance and executive abilities. Overall, we report a robust relationship between executive functioning and navigational skill, with some evidence that men and women may differentially recruit cognitive abilities when navigating a novel environment.