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

AI Summary

AQP4 genetic variants are directly associated with regional brain volumes, brain atrophy, and cognitive performance in Aβ-positive cognitively unimpaired individuals.
AQP4 variants interact with sleep duration, latency, and quality to modulate regional brain volumes and atrophy.
Interactions between AQP4 variants and sleep disturbances are associated with accelerated cognitive decline.

Alzheimers Dement. 2026 Jun;22(6):e71516. doi: 10.1002/alz.71516.

ABSTRACT

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.

PMID:42216479 | DOI:10.1002/alz.71516

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