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.

Fig. 1. Conditional effects of AQP4 SNPs on the relationship between sleep latency and brain Aβ burden.

Moderating effects of the Aquaporin-4 (AQP4) single-nucleotide polymorphisms (SNPs) (A) rs9951307 (dominant model), (B) rs3875089 (dominant model), (C) rs7135406 (dominant model), (D) rs151246 (dominant model) and rs491148, for both the (E) dominant and (F) recessive genetic models, on the relationship between sleep latency (min) and brain Aβ burden. M Minor allele, m major allele. Dominant genetic model: homozygote for the major allele (mm) compared to heterozygote/homozygote for the minor allele (mM or MM). Recessive genetic model: homozygote/heterozygote for the major allele (mm or mM) compared to homozygote for the minor allele (MM). Brain Aβ burden is presented as ¹¹C-Pittsburgh compound B (PiB) positron emission tomography (PET)-like standardized uptake value ratio (SUVR) and as the Before the Centiloid Kernel Transformation (BeCKeT) scale for florbetapir and flutemetamol studies

Fig. 2. Conditional effects of AQP4 SNPs on the relationship between sleep duration and brain Aβ burden.

Moderating effects of Aquaporin-4 (AQP4) single-nucleotide polymorphisms (SNPs) (A) rs72878776 (dominant model), (B) rs491148 (dominant model), and (C) rs2339214 (recessive model) on the relationship between sleep duration (hours) and brain Aβ burden. M, Minor allele; m, major allele. Dominant genetic model: homozygote for the major allele (mm)) compared to heterozygote/homozygote for the minor allele (mM or MM). Recessive genetic model: homozygote/heterozygote for the major allele (mm or mM) compared to homozygote for the minor allele (MM). Brain Aβ burden is presented as ¹¹C-Pittsburgh compound B (PiB) positron emission tomography (PET) like standardized uptake value ratio (SUVR) and as the Before the Centiloid Kernel Transformation (BeCKeT) scale for florbetapir and flutemetamol studies