Dataset Information

Genetic variation in Aquaporin-4 moderates the relationship between sleep and brain A?-amyloid burden.

ABSTRACT: The glymphatic system is postulated to be a mechanism of brain A?-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 A?-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 A?-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 A?-amyloid burden and whether these genetic variants moderated the sleep-A?-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 A?-amyloid burden. This study suggests that AQP4 genetic variation moderates the relationship between sleep and brain A?-amyloid burden, which adds weight to the proposed glymphatic system being a potential A?-amyloid clearance mechanism and suggests that AQP4 genetic variation may impair this function. Further, AQP4 genetic variation should be considered when interpreting sleep-A? relationships.

SUBMITTER: Rainey-Smith SR

PROVIDER: S-EPMC5865132 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Rainey-Smith Stephanie R SR Mazzucchelli Gavin N GN Villemagne Victor L VL Brown Belinda M BM Porter Tenielle T Weinborn Michael M Bucks Romola S RS Milicic Lidija L Sohrabi Hamid R HR Taddei Kevin K Ames David D Maruff Paul P Masters Colin L CL Rowe Christopher C CC Salvado Olivier O Martins Ralph N RN Laws Simon M SM

Translational psychiatry 20180226 1

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 bur ...[more]

PMID: 29479071

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Project description:Background Apolipoprotein E4 (APOE4) is a major genetic risk factor for late-onset Alzheimer disease. However, the mechanisms by which APOE4 affects the brain, underpinning this risk, have not been fully elucidated. Purpose To investigate the influence of APOE4 on global cerebral oxygen extraction fraction (OEF) and possible mediation through amyloid burden by using MRI-based brain oxygen extraction technique. Materials and Methods Participants were enrolled from a longitudinal prospective study, the Biomarkers for Older Controls at Risk for Dementia study (data collected from January 2015 to December 2017), of whom 35% (50 of 143 participants) were APOE4 carriers. OEF was measured by using a T2-relaxation-under-spin-tagging MRI technique with a 3.0-T MRI system. PET acquired with carbon 11-labeled Pittsburgh compound B tracer was available in 119 participants to measure amyloid burden. Cognitive performance was assessed by using domain-specific composite scores including executive function, episodic memory, visual-spatial processing, and language. Linear regression analysis was performed to investigate the relationship between APOE4, OEF, and amyloid burden. The association between OEF and cognitive function was studied for the entire study cohort and separately for the APOE4 carriers and noncarriers. Results A total of 143 cognitively healthy individuals (mean age 6 standard deviation, 69.1 years 6 8.2; 57 men and 86 women) were studied. APOE4 genetic status was associated with lower OEF (noncarriers, 41.1% 6 5.8; one E4 allele, 40.1% 6 4.9; two E4 alleles, 36.7% 6 4.5; P = .03). Furthermore, among APOE4 carriers, lower OEF correlated with lower executive function scores (b = 0.079 z score for each percent change in OEF; P = .03). Amyloid burden and OEF were independently associated with APOE4 but were not associated with one another, suggesting that the effect of APOE4 on OEF is not mediated by amyloid. Conclusion MRI-based brain oxygen extraction shows that cognitively healthy carriers of the apolipoprotein E4 gene manifest diminished brain oxygen extraction capacity independent of amyloid burden. ©RSNA, 2019 Online supplemental material is available for this article.

Project description:BackgroundRecent evidence indicates that disrupted sleep could contribute to the development of Alzheimer's disease by influencing the production and/or clearance of the amyloid-β protein. We set up a case-control study to investigate the association between long-term work-induced sleep disruption, cognitive function, and brain amyloid-β burden.MethodsNineteen male maritime pilots (aged 48-60 years) with chronic work-related sleep disruption and a sex-, age-, and education-matched control sample (n = 16, aged 50-60 years) with normal sleep completed the study. Primary sleep disorders were ruled out with in-lab polysomnography. Additional sleep measurements were obtained at home using actigraphy, sleep-wake logs, and a single-lead EEG device. Cognitive function was assessed with a neuropsychological test battery, sensitive to early symptomatic Alzheimer's disease. Brain amyloid-β burden was assessed in maritime pilots using 18F-flutemetamol amyloid PET-CT.ResultsMaritime pilots reported significantly worse sleep quality (Pittsburgh Sleep Quality Index (PSQI) = 8.8 ± 2.9) during work weeks, compared to controls (PSQI = 3.2 ± 1.4; 95% CI 0.01 to 2.57; p = 0.049). This was confirmed with actigraphy-based sleep efficiency (86% ± 3.8 vs. 89.3% ± 4.3; 95% CI 0.43 to 6.03; p = 0.03). Home-EEG recordings showed less total sleep time (TST) and deep sleep time (DST) during work weeks compared to rest weeks (TST 318.56 (250.21-352.93) vs. TST 406.17 (340-425.98); p = 0.001; DST 36.75 (32.30-58.58) vs. DST 51.34 (48.37-69.30); p = 0.005)). There were no differences in any of the cognitive domains between the groups. For brain amyloid-β levels, mean global cortical standard uptake value ratios of 18F-flutemetamol were all in the normal range (1.009 ± 0.059; 95% CI 0.980 to 1.037), confirmed by visual reads.ConclusionsCapitalizing on the particular work-rest schedule of maritime pilots, this study with a small sample size observed that long-term intermittent sleep disruption had no effects on global brain amyloid-β levels or cognitive function.

Dataset Information

Genetic variation in Aquaporin-4 moderates the relationship between sleep and brain A?-amyloid burden.

Publications

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

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