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

BackgroundApolipoprotein E (<i>APOE</i>) 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.ObjectiveThis study aims to explore the effect of <i>APOE</i> ε4 on dynamic FC (dFC) variability and cognitive performance in AD.MethodsWe analyzed the dFC of AD patients, comparing <i>APOE</i> 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 <i>APOE</i> ε4 and cognitive decline in AD patients.ResultsAD patients carrying the <i>APOE</i> 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 <i>APOE</i> ε4 influences dFC in this brain region, contributing to executive dysfunction in AD.ConclusionsThese findings offer preliminary evidence that <i>APOE</i> ε4 modulates fluctuating communication within the cerebellar lobe and the dFC between the cerebellar lobe and the temporal gyrus in AD.