APOE ε4-related structural vulnerability in mild cognitive impairment: a subsystem-based analysis of the default mode network.
Xiaoming Yang, Jian Lyu, Jubo Wang, Yu Quan
Research Square May 11, 2026 preprint DOI: 10.21203/rs.3.rs-9447482/v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort |
|---|---|
| Sample size | 176 |
| Population | Participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 116 patients with mild cognitive impairment and 60 cognitively normal individuals |
| Topics | Default mode network |
| Keywords | Apolipoprotein e ε4 Dorsomedial prefrontal cortex Mediation analysis Mild cognitive impairment Superior temporal pole |
| Key findings | Among MCI patients, APOE ε4 carriers showed selective atrophy in the DMPFC subsystem (gyrus rectus and superior temporal pole), and TPOsup atrophy mediated 30.43% of the negative effect of APOE ε4 on global cognition. |
Abstract
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. 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. 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. 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.
Comparable studies
Other observational and cohort studies on default mode network, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| A default mode of brain function Normal adult human brain | 2001 | Observational study | |
| Resting-State Functional Connectivity Reflects Structural Connectivity in the Default Mode Network Healthy subjects | 2008 | Observational cohort | |
| Meditation experience is associated with increased cortical thickness Participants with extensive Insight meditation experience and matched controls | 2005 | Observational cohort | n = 20 |
| Meditation experience is associated with differences in default mode network activity and connectivity Experienced meditators and matched meditation-naive controls | 2011 | Observational cohort | |
| The precuneus/posterior cingulate cortex plays a pivotal role in the default mode network: Evidence from a partial correlation network analysis Healthy subjects | 2008 | Observational study |