APOE ε4 influences the dynamic functional connectivity variability and cognitive performance in Alzheimer's disease

Background Apolipoprotein E ( APOE ) ε4 is the most significant genetic risk factor for sporadic Alzheimer's disease (AD). However, its impact on the dynamic changes in resting-state functional connectivity (FC), particularly concerning network formation, interaction, and dissolution over time, remains largely unexplored in AD. Objective This study aims to explore the effect of APOE ε4 on dynamic FC (dFC) variability and cognitive performance in AD. Methods We analyzed the dFC of AD patients, comparing APOE ε4 carriers (n = 33) with non-carriers (n = 41). The whole-brain dFC was assessed by calculating dynamic fractional amplitude of low-frequency fluctuations (dfALFF) and dynamic regional homogeneity (dReHo). To further explore the relationship between cognitive function and dFC in AD patients, we conducted a correlation analysis. Mediation analysis was also performed to determine whether dFC mediates the link between the APOE ε4 and cognitive decline in AD patients. Results AD patients carrying the APOE ε4 exhibited more severe cognitive impairment, along with reduced dReHo and dfALFF in both the left and right posterior cerebellar lobes. In these carriers, the dFC analysis showed lower dFC between the left posterior cerebellar lobe and the left middle temporal gyrus, which was positively correlated with executive function and information processing speed. Additionally, mediation analysis indicated that APOE ε4 influences dFC in this brain region, contributing to executive dysfunction in AD. Conclusions These findings offer preliminary evidence that APOE ε4 modulates fluctuating communication within the cerebellar lobe and the dFC between the cerebellar lobe and the temporal gyrus in AD.