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

Sleep duration and Apolipoprotein E genotype are critical factors influencing Alzheimer's disease progression. This study investigates the interaction between sleep duration and Apolipoprotein E genotype on the functional connectivity of the locus coeruleus in clinically unimpaired older adults with elevated amyloid beta, a population at risk for pre-clinical Alzheimer's disease. The study included 692 clinically unimpaired older adults with elevated amyloid beta participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Study (A4). Resting-state functional MRI data were analysed to construct locus coeruleus-based functional connectivity networks, and a 2 × 2 analysis of covariance was conducted to examine the main and interactive effects of sleep duration (normal versus short sleep) and Apolipoprotein E genotype (ɛ4- versus ɛ4+) on locus coeruleus-functional connectivity. Structural equation modelling was used to explore whether locus coeruleus-functional connectivity mediated the relationship between age and cognitive performance. Significant main effects of sleep duration and Apolipoprotein E genotype on locus coeruleus-functional connectivity were observed in the right temporal pole, middle cingulate cortex, and superior temporal gyrus. An interactive effect of sleep and Apolipoprotein E genotype was noted, influencing left locus coeruleus-functional connectivity in regions in the precentral gyrus, and right locus coeruleus-functional connectivity network in the middle temporal gyrus and lateral orbitofrontal cortex. Mediation analysis revealed that locus coeruleus-functional connectivity in the middle cingulate cortex and lateral orbitofrontal cortex partially mediated age associated cognitive decline. These findings suggest that locus coeruleus-functional connectivity networks, influenced by sleep duration and Apolipoprotein E 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 Alzheimer's disease.