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

Junlin Shen,Qiang Xu,Bing Liu,Peng Zhang,Huaigui Liu,Jiayuan Xu,Lixue Xu,Chunshui Yu,Tianzi Jiang,Wen Qin

doi:10.1007/s00429-017-1377-3

Abstract

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.

Highlights

As a common polygenic disorder, Alzheimer’s disease (AD) is clinically characterized by progressive deterioration of memory and other cognitive abilities, and is pathologically characterized by formation of senile plaques and neurofibrillary tangles (Bird 2008)
We found that Apolipoprotein E (APOE) ε4 carriers had significantly reduced memory quotient (F = 6.71, P = 0.01) than non-ε4 carriers for the main effect of APOE (Fig. S1)
For all hippocampal resting-state functional connectivity (rsFC) with a significant main or In the present study, we systematically investigated the interaction effect of SORL1 and APOE, we calculated main effects and interactions of SORL1 and APOE genetic variations on hippocampal rsFC in healthy young adults

Summary

Introduction

As a common polygenic disorder, Alzheimer’s disease (AD) is clinically characterized by progressive deterioration of memory and other cognitive abilities, and is pathologically characterized by formation of senile plaques and neurofibrillary tangles (Bird 2008). Several previous studies have reported SORL1 × APOE interactions on the risk for AD (Cellini et al 2009; Kimura et al 2009) and on amyloid protein β (Aβ) concentrations in cerebrospinal fluid (CSF) in AD patients (Alexopoulos et al 2011a, b). APOE genotypes have been associated with hippocampal resting-state functional connectivity (rsFC) in healthy adults (Fleisher et al 2009; Heise et al 2014; Sheline et al 2010). It remains unclear whether and how SORL1 genetic variation modulates hippocampal rsFC. Both APOE and SORL1 act on the amyloid precursor protein (APP) pathway (Bohm et al 2015) and affect the hippocampus (Louwersheimer et al 2015; Pievani et al 2011), suggesting a potential interaction between APOE and SORL1

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Results

Conclusion