Differential effects of APOE genotypes on intrinsic functional connectivity of the entorhinal cortex associated with episodic memory in amnestic mild cognitive impairment

Abstract

Background The apolipoprotein E ( APOE ) gene is a well-established genetic susceptibility factor for the conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD). Moreover, entorhinal cortex (ERC) is one of the earliest brain regions of AD pathology that disrupts the formation of episodic memory. The present study was the first to investigate whether there are differential effects of APOE polymorphism on functional connectivity (FC) of ERC and cognition in aMCI. Methods The FC analyses of ERC in whole-brain were performed in 83 aMCI and 88 healthy controls (HC). Results In the ERC network, aMCI with APOE epsilon 4 (ɛ4)-carriers showed decreased FC with the bilateral middle temporal gyrus (MTG) and the right precuneus (PCUN), and the right precentral gyrus (PreCG), while APOE ɛ2-carriers showed increased FC (except decreased FC with the right PreCG) compared to HC. The altered FC between ERC and right MTG correlated with the impairment of episodic memory in aMCI carried APOE ɛ4 and ɛ2 allele. Conclusions These results provide novel evidence that APOE ɛ4 and ɛ2 alleles affect multiple physiopathologic pathways in the ERC network, which aMCI with ɛ4-carriers can accelerate the pathological progression of network-based mechanisms while ɛ2-carriers may play a protective role in contributing to a compensatory mechanism. It further suggests that APOE can appear to indirectly mediate the ERC-MTG neural pathway associated with the impairment of episodic memory in aMCI.