Alzheimer's disease pathogenesis and the role of <i>APOE</i> ε4 in remodeling functional gradients of the default mode network

BackgroundAlzheimer's disease (AD) involves Aβ and tau pathology, initiating years before symptoms. the apolipoprotein E ε4 allele (<i>APOE</i> ε4) is the major genetic risk factor, influencing neurodegeneration and functional network disruption. This study investigates how <i>APOE</i> ε4 modulates the default mode network (DMN)'s hierarchical organization to accelerate cognitive decline.ObjectiveThis study aimed to elucidate how <i>APOE</i> ε4 accelerates AD pathological progression by altering the functional gradient hierarchy of DMN, and to evaluate the potential of DMN gradient abnormalities as an early diagnostic biomarker for AD.MethodsWe enrolled 271 participants, categorized by diagnosis and <i>APOE</i> ε4 status. All underwent neuropsychological assessment, plasma Aβ_42/40 measurement, and resting-state functional MRI. DMN functional gradients were quantified using the BrainSpace toolbox. Statistical analyses included a 2 × 2 factorial design, mediation analysis, and correlation testing with cognitive scores.ResultsA significant Group × Genotype interaction was identified in the right inferior temporal gyrus (RITG). AD patients with <i>APOE</i> ε4 showed the most severe gradient attenuation, while non-carrier patients exhibited compensatory elevation. The RITG gradient correlated with multiple cognitive domains exclusively in <i>APOE</i> ε4 carriers. Altered connectivity between the left superior frontal gyrus (LSFG) and RITG mediated the effect of Aβ burden on gradient disruption.Conclusions<i>APOE</i> ε4 accelerates cognitive decline in AD by specifically disrupting the DMN functional gradient hierarchy, particularly within the right ITG. Amyloid-β deposition contributes to macro-scale DMN topological disorganization by impairing LSFG-RITG functional connectivity. DMN functional gradient mapping provides a sensitive biomarker for early AD diagnosis and a novel target for <i>APOE</i> ε4-targeted interventions.