APOE genotype modulates the impact of sleep duration on locus coeruleus functional connectivity in preclinical Alzheimer’s disease

Sleep duration and Apolipoprotein E (APOE) genotype are critical factors influencing Alzheimer's disease (AD) progression. This study investigates the interaction between sleep duration and APOE genotype on the functional connectivity (FC) of the locus coeruleus (LC) in clinically unimpaired older adults with elevated amyloid beta (CUOA-Aβ+), a population at risk for preclinical AD. The study included 692 CUOA-Aβ+ participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Study (A4). Resting-state functional MRI data were analyzed to construct LC-based FC networks, and a 2 × 2 analysis of covariance was conducted to examine the main and interactive effects of sleep duration (normal vs. short sleep) and APOE genotype (ε4- vs. ε4+) on LC-FC. Structural equation modeling was used to explore whether LC-FC mediated the relationship between age and cognitive performance. Significant main effects of sleep duration and APOE genotype on LC-FC were observed in the right temporal pole, middle cingulate cortex (MCC), and superior temporal gyrus. An interactive effect of sleep and APOE genotype was noted, influencing left LC-FC in regions in the precentral gyrus, and right LC-FC network in the middle temporal gyrus and lateral orbitofrontal cortex (lOFC). Mediation analysis revealed that LC-FC in the MCC and lOFC partially mediated age associated cognitive decline. These findings suggest that LC-FC networks, influenced by sleep duration and APOE genotype, play a crucial role in cognitive aging, particularly in memory function. Understanding these interactions may inform early intervention strategies to preserve cognitive health in older adults at risk for AD.