Apolipoprotein E (APOE) gene serves as an established genetic factor that influence Alzheimer’s disease (AD) onset and progression. Traditionally, APOE ε2 allele is a protective factor while APOE ε4 allele is a destructive factor related to late-onset AD. However, neuropathology mechanism of APOE genotype effects on AD are still unclear, especially ε2 allele effect. In the present study, we investigated the effects of APOE genotypes on amygdala functional connectivity (AFC) network in amnestic mild cognitive impairment (aMCI) patients and cognitively normal (CN) elders, and explore the potential effects of APOE and age on cognitive impairment.A cross-sectional resting-state functional magnetic resonance imaging study of 84 aMCI subjects (including 9 APOE ε2, 45 ε3, 28 ε4 carriers) and demographically matched 124 cognitively normal (CN) elder individuals (including 35 APOE ε2, 43 ε3, 46 ε4 carriers) between the ages of 55 and 80. Voxelwised intrinsic blood oxygenation level–dependent (BOLD) testing the strength of functional connectivity in the AFC network. Multivariate linear regression was used to identify the distinct effects of APOE ε2 and ε4 on the AFC network, as well as the interactive effects of age and APOE genotype on AFC network. Mediation analysis was employed to explore whether AFC network mediated the association between APOE genotypes, age and cognitive impairment.Between two groups, there were no significant difference in the demographic information and gray matter volumes. AMCI patients had significantly decreased connectivity in posterior default mode network (pDMN), sensorimotor cortex and cerebellum, and increased connectivity in anterior DMN, executive control network (ECN), thalamus, middle cingulate cortex. Importantly, the ε2 carriers and ε4 carriers showed convergent effects on right AFC but divergent effects on left AFC network when CN compared to aMCI patients. Interactive effects of APOE genotypes and age on AFC network further revealed neural basis of ten years earlier on the age of onset in aMCI patients. Further, mediation analysis suggested that connectivity strength mediated the effects of APOE genotypes and age on the cognitive function in aMCI patients.

These data suggested convergent and divergent effects of APOE ε2 and ε4 on the underlying neuropathology mechanism of AD. The functional network might modulate the genetic and age influence on cognitive impairment in non-demented elder. The interactive effects of APOE genotype and age on functional network also supported the resource-modulation hypothesis in elder adults.