Protective effect of APOE epsilon 2 on intrinsic functional connectivity of the entorhinal cortex is associated with better episodic memory in elderly individuals with risk factors for Alzheimer's disease

The apolipoprotein E (APOE) epsilon 4 allele associates with accelerating the conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD), whereas the protective APOE epsilon 2 allele appears to be against the disease. Moreover, entorhinal cortex (ERC) is one of the earliest brain regions of AD pathology that disrupts the formation of episodic memory. To investigate the effects of APOE epsilon 2 and epsilon 4 alleles on functional connectivity (FC) of ERC and cognition in aMCI. Methods The FC analyses of ERC were performed in 83 aMCI (9 epsilon 2-carrier, 44 epsilon 3 epsilon 3, and 30 epsilon 4-carrier) and 88 healthy controls (HC, 15 epsilon 2-carrier, 40 epsilon 3 epsilon 3, and 33 epsilon 4-carrier). Multiple linear regression model was performed between the altered ERC connectivities and cognition. In the ERC network, aMCI with epsilon 4-carriers showed decreased FC in the bilateral middle temporal gyrus (MTG), right precuneus, and right precentral gyrus (PreCG), while epsilon 2-carriers showed increased FC in these regions (except the right PreCG) compared to HC. The altered FC between ERC and right MTG correlated with episodic memory performance in aMCI carried epsilon 2 and epsilon 4 alleles. These results suggest that the effects of APOE on the ERC network are closely linked to the role of this gene on AD risk, which aMCI with epsilon 4-carriers can accelerate the pathological progression of network-based mechanisms while epsilon 2-carriers may play a protective role in contributing to a compensatory mechanism. It further suggests that APOE can appear to directly affect the ERC-MTG neural pathway associated with the impairment of episodic memory in aMCI.