0067 Longitudinal Impact of Aquaporin-4 Gene Variants on Perivascular Diffusivity

Abstract Introduction Aquaporin-4 water channels play a key role in glymphatic clearance of brain metabolites, and their variants may alter glymphatic function and interstitial fluid dynamics. We investigated how aquaporin-4 variants affect changes in diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) that estimates directional water diffusivity within the perivascular space, as well as the mediating role of DTI-ALPS between aquaporin-4 diplotype and cognitive performance changes, 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. Three aquaporin-4 variants (rs16942851, rs335929, and rs335931) were used to categorize participants into three groups according to the aquaporin-4 diplotype: major-diplotype (n=318), hetero-diplotype (n=456), and minor-diplotype (n=164). Longitudinal changes in DTI-ALPS were examined using linear mixed model with random intercepts, adjusting for age, sex, body mass index, education, Apolipoprotein E ɛ4 carrier status, current drinking, current smoking, hypertension, and diabetes, and total sleep time, sleep efficiency, and the baseline values of DTI-ALPS. Mediation analyses were performed to determine whether DTI-ALPS mediated the association between aquaporin-4 diplotype and cognitive changes. Results The minor-diplotype exhibited a significantly greater decline in DTI-ALPS over time than the major-diplotype (–0.133, [–0.23, –0.04], P=0.007), whereas the hetero-diplotype showed no difference (–0.035, [–0.11, 0.04], P=0.349). Longitudinal changes in DTI-ALPS significantly mediated the effects of aquaporin-4 diplotype on changes in visual reproduction scores, including immediate recall (-0.053, [-0.096, -0.011], P=0.012), delayed recall (-0.053, [-0.096, -0.009], P=0.009), and recognition (-0.017, [-0.033, -0.001]; P=0.010). Conclusion Aquaporin-4 diplotype was associated with longitudinal declines in DTI-ALPS, suggesting variant-related vulnerability in glymphatic function. Furthermore, the mediation results indicate that reduced perivascular diffusivity could be a pathway that underlies the association between aquaporin-4 variants and visual memory change over time. 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).