Evidence for direct and sleep-moderated relationships between aquaporin-4 genetic variants and Alzheimer's disease phenotypes

Tenielle Porter; Ayeisha Milligan Armstrong; Eleanor K O'Brien; Vincent Doré; Pierrick Bourgeat; Mitchell Turner; Paul Maruff; Christopher C Rowe; Belinda M Brown; Victor L Villemagne; Stephanie R Rainey-Smith; Simon M Laws; AIBL Research Group

doi:10.1002/alz.71516

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Evidence for direct and sleep-moderated relationships between aquaporin-4 genetic variants and Alzheimer's disease phenotypes

Journal article

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Evidence for direct and sleep-moderated relationships between aquaporin-4 genetic variants and Alzheimer's disease phenotypes

Tenielle Porter, Ayeisha Milligan Armstrong, Eleanor K O'Brien, Vincent Doré, Pierrick Bourgeat, Mitchell Turner, Paul Maruff, Christopher C Rowe, Belinda M Brown, Victor L Villemagne, …

Alzheimer's & dementia, Vol.22(6), e71516

2026

DOI: https://doi.org/10.1002/alz.71516

PMID: 42216479

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Abstract

Amyloid beta

aquaporin-4 (AQP4)

brain volume

cognition

glymphatic system

sleep

Introduction Variants in the aquaporin-4 gene (AQP4) have been associated with Alzheimer's disease (AD) diagnosis, cognition, and brain amyloid beta (Aβ) and may affect the sleep and Aβ relationship. Their association with other AD-related phenotypes/disease progression remain largely unknown. Methods Associations between AQP4 variants, self-reported sleep measures, and AD-related phenotypes in cognitively unimpaired individuals with evidence of Aβ accumulation were examined using data from the Australian Imaging, Biomarkers and Lifestyle study. Results AQP4 variants were directly associated with regional brain volumes, atrophy, and cognition. They were also associated with differences in regional brain volumes and atrophy in interaction with sleep duration, latency, and quality. Finally, AQP4 variants were associated with cognitive decline in interaction with sleep disturbances. Discussion These findings support a relationship between AQP4 and AD phenotypes, both directly and through their interaction with sleep. Highlights ∙ This was multimodal study of at-risk individuals integrating genetics, neuroimaging, cognition, and sleep. ∙ AQP4 genetic variants were associated with cognition, both directly and through interactions with sleep quality. ∙ Sleep duration, latency onset, and global quality consistently moderated the associations between AQP4 genetic variants and cognition and brain volumetrics. ∙ Α broad relationship was identified between AQP4 genetic variation and AD, with sleep as a potential modifier.

Details

Title: Evidence for direct and sleep-moderated relationships between aquaporin-4 genetic variants and Alzheimer's disease phenotypes
Authors/Creators: Tenielle Porter - Curtin University
Ayeisha Milligan Armstrong - Curtin University
Eleanor K O'Brien - Edith Cowan University
Vincent Doré - Edith Cowan University
Pierrick Bourgeat - Australian e-Health Research Centre
Mitchell Turner - Edith Cowan University
Paul Maruff - The University of Melbourne
Christopher C Rowe - Austin Health
Belinda M Brown - Murdoch University
Victor L Villemagne - Edith Cowan University
Stephanie R Rainey-Smith - Edith Cowan University
Simon M Laws - Edith Cowan University
AIBL Research Group
Publication Details: Alzheimer's & dementia, Vol.22(6), e71516
Grant note: Alzheimer's Drug Discovery Foundation GNT2001320 / the NHMRC Alzheimer's Association (USA) GNT1161706 / the NHMRC GNT1197315 / NHMRC Investigator
Identifiers: 991005886493907891
Murdoch Affiliation: Research and Innovation Office; Centre for Healthy Ageing
Language: English
Resource Type: Journal article

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