Ventral hippocampal-postcentral gyrus functional connectivity mediates the association of APOE ε4 gene dose, depressive symptoms, and cognitive function in mild cognitive impairment with subsyndromal depression.

BACKGROUND: The apolipoprotein E (APOE) +4 allele is a major genetic risk factor for mild cognitive impairment (MCI) and is associated with hippocampal dysfunction. However, its effects on hippocampal subregional functional connectivity (FC) and clinical manifestations in MCI patients with subsyndromal depression (MCID) remain unclear. METHODS: In this study, 88 patients with MCID were stratified into APOE+4 homozygotes (n = 12), heterozygotes (n = 31), and non-carriers (n = 45). Resting-state FC of the dorsal (dHIP) and ventral hippocampus (vHIP) was examined. Mediation analyses were conducted to investigate the effect of neurological biomarkers on APOE +4 gene dose, depressive symptoms with cognitive function in MCID. RESULTS: Compared with non-carriers, APOE +4 homozygotes showed decreased FC between the left vHIP and the left inferior temporal gyrus and right precentral gyrus, while heterozygotes showed decreased FC between the left vHIP and the right middle frontal gyrus and left cerebellum. In addition, APOE +4 homozygotes exhibited a gene dose-dependent reduction in FC between the vHIP and the left postcentral gyrus (PoCG) compared with heterozygotes. Importantly, vHIP-PoCG FC mediated the relationship between depressive symptoms and cognitive impairment, and between APOE +4 gene dose and cognitive impairment in MCID patients. CONCLUSION: These findings suggest that reduced vHIP-PoCG FC may represent a candidate neuroimaging correlate in MCID and may underlie APOE +4-related vulnerability to depressive and cognitive symptoms. Moreover, the mediating effect of vHIP-PoCG FC may partly account for the association among APOE +4 gene dose, depressive symptoms, and cognitive impairment in MCID.