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) ε4 allele associates with accelerating the conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD), whereas the protectiveAPOEε2 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 ε2 and ε4alleles on functional connectivity (FC) of ERC and cognition in aMCI. Methods The FC analyses of ERC were performed in 83 aMCI (9 ε2-carrier, 44 ε3ε3, and 30 ε4-carrier) and 88 healthy controls (HC, 15 ε2-carrier, 40 ε3ε3, and 33 ε4-carrier). Multiple linear regression model was performed between the altered ERC connectivities and cognition. In the ERC network, aMCI with ε4-carriers showed decreased FC in the bilateral middle temporal gyrus (MTG), right precuneus, and right precentral gyrus (PreCG), while ε2-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 ε2 and ε4 alleles. These results suggest that the effects ofAPOEon the ERC network are closely linked to the role of this gene on AD risk, which aMCI with ε4-carriers can accelerate the pathological progression of network-based mechanisms while ε2-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.