Abstract
BACKGROUND AND OBJECTIVES: The aquaporin-4 (AQP4) water channel plays an integral role in clearing brain waste. However, little is known about whether variations in the AQP4 gene contributes to brain health or dementia risk. We aimed to determine whether a functional AQP4 haplotype was associated with cognition, brain volumes, or incident dementia. METHODS: This study included participants from two prospective cohort studies. Firstly, participants from the Original, Offspring, New Offspring Spouse, and Generation 3 cohorts from the Framingham Heart Study (FHS; enrolled 1948-2005) were included with dementia follow-up until 2022. Original FHS participants were from Framingham, Massachusetts at the time of enrollment. Analyses were replicated for brain MRI outcomes and incident dementia with UK Biobank participants (enrolled 2006-2010) who were followed until 2022. All participants were dementia-free at the time of cognitive assessment, brain MRI, and commencement of dementia follow-up. Linear regression models were conducted to analyze the associations between AQP4 and the cognitive and brain MRI outcomes. Cox proportional hazard regression models were conducted to analyze the association between AQP4 and incident all-cause dementia risk. Data analysis spanned February 2023 to July 2025. RESULTS: The FHS sample comprised 3,847 participants (65% homozygote major, 31% heterozygote, 4% homozygote minor) with cognitive testing (mean age 61±11 years; 54% women); 3,332 had brain MRI. Heterozygotes displayed better verbal episodic memory (β[95% CI], 0.32 [0.09, 0.55], p =0.007, N=1,201) and larger hippocampal volumes (β[95% CI], 0.09 [0.02, 0.16], p =0.012, N=1,052) compared to homozygote majors. Similar findings were observed in the UK Biobank; homozygote minors displayed larger hippocampal volumes (β[95% CI], 0.05 [<0.01, 0.11], p =0.035, N=32,219) and lower amounts of DTI measured free water (β[95% CI], -0.09 [-0.16, - 0.03], p =0.005, N=31,807) compared to homozygote majors. Heterozygotes displayed a statistically significant lower rate of incident all-cause dementia (HR=0.93, 95% CI [0.88, 0.98], p =0.012, N=114,868, incident cases=5,625) compared to homozygote majors. DISCUSSION: Carrying at least one minor allele at an AQP4 haplotype (homozygote minors or heterozygotes) was linked to better verbal episodic memory, larger hippocampal volumes, lower amounts of free water, and lower dementia risk. Further studies are required to replicate these results amongst diverse samples.