Although previous studies have investigated the effects of the apolipoprotein E (APOE) ɛ4 genotype on the default mode network (DMN) in the Alzheimer's disease (AD) spectrum, it is still unclear how the APOE genotype regulates the DMN and subsequently affects cognitive decline in the AD spectrum. One hundred sixty-nine subjects with resting-state functional magnetic resonance imaging data and neuropsychological test scores were selected from the Alzheimer's Disease Neuroimaging Initiative. The main effects and interaction of the APOE genotype and disease status on the DMN were explored. A moderation analysis was performed to investigate the relationship among the APOE genotype, DMN connectivity, and cognition. Additionally, the pair-wised DMN connectivity was used to classify AD spectrum, and the classification accuracy was validated. Compared to APOEɛ4 non-carriers, APOEɛ4 carriers showed the opposite trajectory of DMN connectivity across the AD spectrum. Specifically, the strengths in the posterior cingulate cortex (PCC) connecting with the right precuneus, insular, and fusiform area (FFA) were positively correlated with Mini-Mental State Examination (MMSE) scores in APOEɛ4 non-carriers but not in APOEɛ4 carriers. Furthermore, PCC-right FFA connectivity could moderate the effects of the APOE genotype on MMSE scores across the disease groups. More importantly, using a receiver operating characteristic analysis, these altered connectivities yielded strong classification powers in a pathological stage-dependent manner in the AD spectrum. These findings first identified the intrinsic DMN connectivity moderating the effect of the APOE genotype on cognition and provided a pathological stage-dependent neuroimaging biomarker for early differentiation of the AD spectrum.
Keywords: Alzheimer’s disease; apolipoprotein E; classification; moderation analysis; resting-state functional magnetic resonance imaging.