Date of Award
Bachelor of Science (Medical Science) Honours
School of Medical and Health Sciences
Field of Research Code
Alzheimer’s disease (AD) is widely recognised as a growing global health issue with far ranging social and economic implications. The accumulation of Amyloid-β (Aβ) in the brain is a pathological hallmark of AD. A recently discovered lymphatic–like system in the central nervous system (termed the glymphatic system) has been postulated to be both implicit in the clearance of Aβ from the brain, and most effective during sleep—making sleep an important consideration in the investigation of AD. Central nervous system expressed water channel proteins, namely Aquaporin 1 and 4, have been suggested to play a pivotal role in glymphatic function and thus, clearance of Aβ from the brain. However, to-date this has only been investigated in AD rodent models and one human study of aquaporin/Aβ protein co-localisation in post mortem brain tissue.
To partially address this gap in knowledge, the current study sought to investigate whether genetic variations (single nucleotide polymorphisms, SNPs) within the genes encoding aquaporin 1 (AQP1) and aquaporin 4 (AQP4), were associated with AD risk, brain Aβ burden and self-reported sleep parameters. Further, this study aimed to determine whether genetic variation moderated the relationship between sleep parameters and brain Aβ burden. This study was observational and cross-sectional in design, and utilised Genome-Wide Association Study, Pittsburgh Sleep Quality Index (PSQI), and Aβ positron emission tomography data from the larger Australian Imaging, Biomarkers and Lifestyle (AIBL) study.
Genetic variation in AQP1 and AQP4 SNPs was not associated with either an increased AD risk or differences in brain Aβ burden. However, genetic variation in AQP4, specifically rs12968026, was associated with altered, self-reported, “overall” sleep quality (PSQI total score). Further, this study reports that several SNPs in AQP1 and AQP4 moderate the conditional effect that three PSQI-determined sleep parameters, namely, sleep latency (time taken to fall asleep, in minutes), sleep duration (length of sleep, in hours) and daytime dysfunction (disruption of daytime activities due to sleepiness), had on brain Aβ burden.
Taken together, the results of this study add weight to the argument that the glymphatic system, is a major biological mechanism underpinning Aβ clearance from the brain. The findings also engender a greater understanding of what factors may moderate a sleep-AD phenotype relationship, and suggest that interventions targeted at improving suboptimal sleep parameters may be most effective at delaying AD onset when tailored to the genetics of the individual.
Mazzucchelli, G. N. (2017). Impact of aquaporin (AQP1 and AQP4) genetic variation on the relationship between sleep quality and Alzheimer’s disease pathological hallmarks. https://ro.ecu.edu.au/theses_hons/1500