Genetic variation in Aquaporin-4 moderates the relationship between sleep and brain Aβ-Amyloid burden

Stephanie R. Rainey-Smith, Gavin N. Mazzucchelli, Victor L. Villemagne, Belinda M. Brown, Tenielle Porter, Michael Weinborn, Romola S. Bucks, Lidija Milicic, Hamid R. Sohrabi, Kevin Taddei, David Ames, Paul Maruff, Colin L. Masters, Christopher C. Rowe, Olivier Salvado, Ralph N. Martins, Simon M. Laws*, The AIBL Research Group

*Corresponding author for this work

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number47
Pages (from-to)1-11
Number of pages11
JournalTranslational Psychiatry
Issue number1
Publication statusPublished - 1 Dec 2018


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Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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Rainey-Smith, S. R., Mazzucchelli, G. N., Villemagne, V. L., Brown, B. M., Porter, T., Weinborn, M., ... The AIBL Research Group (2018). Genetic variation in Aquaporin-4 moderates the relationship between sleep and brain Aβ-Amyloid burden. Translational Psychiatry, 8(1), 1-11. [47].