Apolipoprotein E ε4 Specifically Modulates the Hippocampus Functional Connectivity Network in Patients With Amnestic Mild Cognitive Impairment

Abstract

The presence of both apolipoprotein E (APOE) ε4 allele and amnestic mild cognitive impairment (aMCI) are considered to be risk factors for Alzheimer’s disease (AD). Numerous neuroimaging studies have suggested that the modulation of APOE ε4 affects intrinsic functional brain networks, both in healthy populations and in AD patients. However, it remains largely unclear whether and how ε4 allele modulates the brain’s functional network architecture in subjects with aMCI. Using resting-state functional magnetic resonance imaging (fMRI) and graph-theory approaches-functional connectivity strength (FCS), we investigate the topological organization of the whole-brain functional network in 28 aMCI ε4 carriers and 38 aMCI ε3ε3 carriers. In the present study, we first observe that ε4-related FCS increases in the right hippocampus/parahippocampal gyrus (HIP/PHG). Subsequent seed-based resting-state functional connectivity (RSFC) analysis revealed that, compared with the ε3ε3 carriers, the ε4 carriers had lower or higher RSFCs between the right HIP/PHG seed and the bilateral medial prefrontal cortex (MPFC) or the occipital cortex, respectively. Further correlation analyses have revealed that the FCS values in the right HIP/PHG and lower HIP/PHG-RSFCs with the bilateral MPFC were significantly correlated with the impairment of episodic memory and executive function in the aMCI ε4 carriers. Importantly, the logistic regression analysis showed that the HIP/PHG-RSFC with the bilateral MPFC predicted aMCI-conversion to AD. These findings suggest that the APOE ε4 allele may modulate the large-scale brain network in aMCI subjects, facilitating our understanding of how the entire assembly of the brain network reorganizes in response to APOE variants in aMCI. Further longitudinal studies need to be conducted, in order to examine whether these network measures could serve as primary predictors of conversion from aMCI ε4 carriers to AD.