Abstract
Background
Accumulating evidence suggests that rather than simply manifesting as a comorbidity of Alzheimer's disease (AD), suboptimal sleep actually contributes to the pathogenesis of the disease. One postulated mechanism underlying this association involves clearance of brain Aβ-amyloid (Aβ) via the glymphatic system during sleep. The water-channel proteins, Aquaporin (AQP) -1 and -4, are proposed to play a role in glymphatic system-mediated clearance of brain Aβ. Our own work suggests that genetic variation of AQP4 moderates the relationship between sleep and brain Aβ burden in humans. However, currently, there is a paucity of literature regarding the impact of AQP1 genetic variation on sleep, brain Aβ burden and their relationship to each other: a knowledge gap that the current study sought to address.
Methods
A cross-sectional observational study was undertaken in cognitively normal older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study (N = 222). Genetic variants in AQP1 were investigated with respect to self-reported Pittsburgh Sleep Quality Index sleep parameters, positron emission tomography-derived brain Aβ burden and whether these genetic variants moderated the sleep-Aβ burden relationship.
Results
The AQP1 variant, rs28362727, moderated the effect of sleep latency on brain Aβ burden. Carriage of the minor allele (rs28362727-C), in combination with longer time to fall asleep, was associated with an elevated cerebral Aβ load, to a level that would be classified as ‘high’ (PiB-like Standardized Uptake Value Ratio (SUVR) > 1.4) if time to fall asleep exceeded 30-minutes (SUVR approaching 1.7 at 35-minutes latency). This association was observably stronger in homozygotes, suggesting a potential gene-dosage effect.
Conclusions
This study suggests that AQP1 genetic variation moderates the relationship between sleep and brain Aβ burden, which adds weight to the proposed glymphatic system being a potential Aβ clearance mechanism, and suggests that AQP1 genetic variation may impair this function. Further, AQP1 genetic variation warrants consideration when interpreting sleep-Aβ relationships.