APOE ε4-related structural vulnerability in mild cognitive impairment: a subsystem-based analysis of the default mode network

Background Mild cognitive impairment (MCI) is a critical prodromal stage of progressive cognitive decline. As a core cognitive brain network, the default mode network (DMN) exhibits structural alterations in MCI that are closely associated with cognitive impairment. Apolipoprotein E ε4 (APOE ε4) , the strongest genetic risk factor for pathological cognitive decline, has been shown to disrupt the structural integrity of the DMN’s three core subsystems: the Midline Core, Medial Temporal Lobe (MTL), and Dorsomedial Prefrontal Cortex (DMPFC) subsystems. However, the subsystem-specific effects of APOE ε4 and the cognitive mechanisms through which they operate in MCI remain unclear. Methods We enrolled 176 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including 116 patients with MCI and 60 cognitively normal (CN) individuals, with balanced APOE ε4 carrier status within each diagnostic group. Standardized volumes of eight DMN regions were analyzed using permutational multivariate analysis of variance (PERMANOVA) to test diagnosis-by-genotype interactions, followed by false discovery rate (FDR)-corrected univariate analyses and multiple linear regression to identify regional volume differences. Bootstrap-based mediation analysis and receiver operating characteristic (ROC) analysis were further performed to examine clinical relevance. Results A significant diagnosis-by- APOE ε4 interaction was observed in the global structural pattern of the DMN, primarily driven by the DMPFC and MTL subsystems. Among patients with MCI, APOE ε4 carriers exhibited selective atrophy within the DMPFC subsystem, specifically in the gyrus rectus (REC) and superior temporal pole (TPOsup), relative to non-carriers. Critically, TPOsup atrophy mediated 30.43% of the negative effect of APOE ε4 on global cognition, as measured by the Mini-Mental State Examination (MMSE), and was significantly associated with impaired orientation. Conclusion The TPOsup may represent a key neural hub linking APOE ε4 to cognitive decline in MCI and may serve as a specific imaging marker for risk stratification in this population.