Search

The sortilin-related receptor 1 (SORL1) gene has been associated with late-onset Alzheimer's disease (LOAD) and structural impairments in several ethnic populations. However, how this gene affects brain function properties remains unclear. We investigated associations of SORL1 rs2070045 with functional connectivity density (FCD) in healthy young adults. This single-nucleotide polymorphism was selected because it is the SORL1 variant that has been frequently associated with LOAD in several populations, including the Chinese Han population. A total of 275 healthy young Chinese Han subjects with successful genotyping and MRI examinations were included. The effect of SORL1 rs2070045 was explored using a voxel-wise FCD analysis. A significant effect of SORL1 rs2070045 on the FCD was found in the right inferior temporal gyrus. The risk G allele carriers of the rs2070045 exhibited a lower FCD than the protective TT carriers. This effect was independent of the status of apolipoprotein E. This study provides the first evidence that the SORL1 gene is associated with brain FCD differences in healthy young adults. In the genetic risk subjects, connectivity impairment already starts during young adulthood, which may predispose the risk allele carriers to be susceptible to LOAD after several decades.

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. Electronic supplementary material The online version of this article (doi:10.1007/s00429-017-1377-3) contains supplementary material, which is available to authorized users.