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 Methods: Associations between genetic variation in glymphatic pathway-related genes ( Results: At the single-variant level, 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.