Abstract Introduction Genetic variants of aquaporin-4 may influence glymphatic clearance through water transport, yet their longitudinal effects on brain structure and cognition are unclear. We investigated how aquaporin-4 variants affect changes in cognition, and mean diffusivity measured from diffusion tensor imaging (DTI), as well as the mediating role of these neuroimaging measures, over four years in a community-based cohort. Methods We studied 938 adults (mean age 58±6 years; 480 women) who underwent DTI and cognitive assessments at baseline and four-year follow-up. To examine the effect of aquaporin-4 variants, we selected three aquaporin-4 variants (rs16942851, rs335929, and rs335931). Participants were categorized into two haplotypes (TAA major, GCG minor). We assessed proportional changes in cognition, and mean diffusivity, and performed mediation analyses to determine whether these imaging markers mediated the association between haplotypes and cognitive decline. A multiple linear regression model was used to determine statistical significance, adjusting for age, sex, body mass index, education, Apolipoprotein E ɛ4 carrier status, current drinking, current smoking, hypertension, and diabetes at baseline. Results Individuals with the minor haplotype showed significantly reduced mean diffusivity in the right orbital inferior frontal gyrus (−1.71% 95% confidence interval −5.48 to −1.81), right insula (−0.97% −1.56 to −0.37), right choroid plexus (−2.12% −3.35 to −0.89), and left pericalcarine white matter (−0.80% −1.19 to −0.41), along with greater declines in story recall-recognition (−2.43% −4.07 to −0.80) and digit symbol coding (−2.08% −3.60 to −0.56, all corrected P-values 0.05). Mediation analysis indicated that reduced mean diffusivity in the right orbital inferior frontal gyrus and right choroid plexus, mediated the relationship between haplotypes and sustained attention decline, while changes in the left pericalcarine area mediated verbal memory decline. Conclusion Aquaporin-4 variants appear to influence microstructural integrity and cognitive performance over time, suggesting a potential genetic target for modulating perivascular clearance and mitigating neurodegenerative risk. Support (if any) This study was also conducted with bioresources from National Biobank of Korea, the Center for Disease Control and Prevention, Republic of Korea (NBK-2020-093 and NBK-2021-014). This research was supported by the Korea Centers for Disease Control and Prevention (2011-E71004-00, 2012-E71005-00, 2013-E71005-00, 2014-E71003-00, 2015-P71001-00, 2016-E71003-00, 2017-E71001-00, and 2018-E7101-00).
Paik et al. (Fri,) studied this question.