Genetic variation in the glymphatic pathway predicts cognition and neurodegeneration in preclinical Alzheimer's disease

Background Impaired glymphatic clearance has been implicated in Alzheimer’s disease (AD) through reduced clearance of amyloid-β (Aβ) and other metabolites from the brain. Mislocalisation of aquaporin-4 (AQP4), a water channel protein anchored to astrocytic endfeet by the dystrophin-associated complex (DAC), has been linked to increased Aβ accumulation, neurodegeneration and cognitive impairment. In animal models, genetic ablation of DAC subunits, leading to AQP4 mislocalisation, increases Aβ accumulation. Genetic variation in AQP4 has been examined in the context of AD, but variation in key DAC genes has not been systematically investigated in humans. This study examined whether variation within glymphatic pathway genes is associated with AD-related phenotypes in individuals on the AD trajectory. Methods Associations between genetic variation in glymphatic pathway-related genes ( AQP4 and three DAC genes: DAG1 , DTNA , and SNTA1 ) and brain Aβ burden, cognition and regional brain volumes were analysed in two longitudinal cohorts of cognitively unimpaired older adults who were Aβ-positive or demonstrated ongoing Aβ accumulation. Linear regression models assessed cross-sectional and longitudinal outcomes within each cohort, followed by a meta-analysis. Pathway-based glymphatic genetic risk scores (G-GRS) were constructed to assess cumulative genetic impact. Results At the single-variant level, AQP4 , DTNA , and DAG1 showed significant associations with cognition, grey matter atrophy, and ventricular volume after correction for multiple testing. Variants in AQP4 (rs10502478 and rs10164026) were associated with differences in cross-sectional PACC scores. Whilst rs45556134 within DTNA was associated with grey matter atrophy. Further, six variants (rs13079082 DAG1 , rs8092794, rs17642885, rs7233779, rs78837792 and rs79500711 DTNA ) were associated with cross-sectional ventricular volumes. At the polygenic level, higher G-GRS were associated with lower grey matter volume, faster grey matter atrophy, larger ventricular volumes and lower cognitive composite scores. Conclusions Variation within key glymphatic pathway genes is associated with early differences in cognition and neurodegeneration-related brain measures in cognitively unimpaired Aβ-positive older adults. These findings support a contributory role for glymphatic pathway dysfunction in early AD-related brain vulnerability and identify glymphatic pathway genetic risk as a potential marker for risk stratification. A limitation of this study is the absence of direct experimental measures of glymphatic clearance function, which will be required to confirm the functional impact of these genetic findings.