Genetic variation in Aquaporin-4 moderates the relationship between sleep and brain Aβ-amyloid burden
- PMID: 29479071
- PMCID: PMC5865132
- DOI: 10.1038/s41398-018-0094-x
Genetic variation in Aquaporin-4 moderates the relationship between sleep and brain Aβ-amyloid burden
Abstract
The glymphatic system is postulated to be a mechanism of brain Aβ-amyloid clearance and to be most effective during sleep. Ablation of the astrocytic end-feet expressed water-channel protein, Aquaporin-4, in mice, results in impairment of this clearance mechanism and increased brain Aβ-amyloid deposition, suggesting that Aquaporin-4 plays a pivotal role in glymphatic function. Currently there is a paucity of literature regarding the impact of AQP4 genetic variation on sleep, brain Aβ-amyloid burden and their relationship to each other in humans. To address this a cross-sectional observational study was undertaken in cognitively normal older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Genetic variants in AQP4 were investigated with respect to self-reported Pittsburgh Sleep Quality Index sleep parameters, positron emission tomography derived brain Aβ-amyloid burden and whether these genetic variants moderated the sleep-Aβ-amyloid burden relationship. One AQP4 variant, rs72878776, was associated with poorer overall sleep quality, while several SNPs moderated the effect of sleep latency (rs491148, rs9951307, rs7135406, rs3875089, rs151246) and duration (rs72878776, rs491148 and rs2339214) on brain Aβ-amyloid burden. This study suggests that AQP4 genetic variation moderates the relationship between sleep and brain Aβ-amyloid burden, which adds weight to the proposed glymphatic system being a potential Aβ-amyloid clearance mechanism and suggests that AQP4 genetic variation may impair this function. Further, AQP4 genetic variation should be considered when interpreting sleep-Aβ relationships.
Conflict of interest statement
C.L.M. is an advisor to Prana Biotechnology Ltd and a consultant to Eli Lilly. P.M. is a full-time employee of Cogstate Ltd. D.A. has served on scientific advisory boards for Novartis, Eli Lilly, Janssen, and Pfizer Inc. R.N.M. is a consultant to Alzhyme. C.C.R. has served on scientific advisory boards for Bayer Pharma, Elan Corporation, GE Healthcare and AstraZeneca; has received speaker honoraria from Bayer Pharma and GE Healthcare; and has received research support from Bayer Pharma, GE Healthcare, Piramal Lifesciences and Avid Radiopharmaceuticals. H.R.S. has received/is receiving remunerations from the Australian Alzheimer’s Research Foundation for working on several of their clinical trials associated with Takeda, Merck and AstraZeneca and Eli Lilly. VLV served as a consultant for Bayer Pharma; and received research support from a NEDO grant from Japan. S.M.L. has previously been a paid consultant to Alzhyme. The remaining authors declare that they have no conflict of interest.
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