Exploring the impact of APOE ɛ4 on functional connectivity in Alzheimer’s disease across cognitive impairment levels

The apolipoprotein E (APOE) ɛ4 allele is a recognized genetic risk factor for Alzheimer's Disease (AD). Studies have shown that APOE ɛ4 mediates the modulation of intrinsic functional brain networks in cognitively normal individuals and significantly disrupts the whole-brain topological structure in AD patients. However, how APOE ɛ4 regulates brain functional connectivity (FC) and consequently affects the levels of cognitive impairment in AD patients remains unknown. In this study, we systematically analyzed functional magnetic resonance imaging (fMRI) data from two distinct cohorts: an In-house dataset includes 59 AD patients (73.37 ± 6.42 years), and the ADNI dataset includes 117 AD patients (74.91 ± 7.91 years). Experimental comparisons were conducted by grouping AD patients based on both APOE ɛ4 status and cognitive impairment levels of AD. Network-Based Statistic (NBS) method and the Graph Neural Network Explainer (GNN-Explainer) were combined to identify significant FC changes across different comparisons. Importantly, the GNN-Explainer method was introduced as an enhancement over the NBS method to better model complex high-order nonlinear characteristics for discovering FC features that significantly contribute to classification tasks. The results showed that APOE ɛ4 primarily influenced temporal lobe FCs, while it influenced different cognitive impairment levels of AD by adjusting prefrontal-parietal FCs. These findings were validated by p-values < 0.05 from NBS method, and 5-fold cross-validation along with ablation studies from the GNN-Explainer method. In conclusion, our findings provide new insights into the role of APOE ɛ4 in altering FC dynamics during the progression of AD, highlighting potential targets for early intervention.