Modulation of APOE and SORL1 genes on hippocampal functional connectivity in healthy young adults

Apolipoprotein E (APOE) and sortilin-related receptor (SORL1) genes act on the same metabolic pathway and have been associated with Alzheimer's disease (AD) characterized by hippocampal impairment. Although the effects of APOE on hippocampal resting-state functional connectivity (rsFC) have been reported, the main effects of SORL1 and SORL1 × APOE interactions on hippocampal rsFC in healthy subjects remain largely unknown. Here, we systematically investigated the main effects of SORL1 rs2070045, and APOE, and their interaction effects on hippocampal rsFC in healthy young adults. The main effect of APOE showed that risk ε4 carriers had decreased positive hippocampal rsFC with the precuneus/posterior cingulate cortex and subgenual anterior cingulate cortex, and increased positive hippocampal rsFC with the sensorimotor cortex compared with non-ε4 carriers. The main effect of SORL1 showed that risk G-allele carriers had decreased positive rsFC between the hippocampus and middle temporal gyrus compared with TT carriers. No significant additive interaction was observed. Instead, significant SORL1 × APOE non-additive interaction was found in negative rsFC between the hippocampus and inferior frontal gyrus. Compared with subjects with TT genotype, SORL1 G-allele carriers had a stronger negative rsFC in APOE ε4 carriers, but a weaker negative rsFC in APOE non-ε4 carriers. These findings suggest that SORL1 and APOE genes modulate different hippocampal rsFCs and have a complex interaction. The SORL1- and APOE-dependent hippocampal connectivity changes may at least partly account for their association with AD.