Spatial organization of AQP4 water channel expression in the human brain.

Aquaporin-4 (AQP4) water channels support the glymphatic system, a brain-wide pathway that clears cerebral waste products. Here, we use AQP4 gene expression to reconstruct a whole-brain glymphatic-related topography and link it to vascular physiology, glioma, and vulnerability to neurodegenerative diseases. We find that AQP4 expression is highly organized across the brain, peaking in subcortical, ventral, and periventricular territories, consistent with a clearance axis near cerebrospinal fluid reservoirs and perivascular interfaces. Linking AQP4 expression to vascular organization, AQP4-enriched regions show lower normative blood perfusion, but lie close to areas commonly affected by cerebral small vessel disease. Turning to neurodegeneration, we find that atrophy patterns colocalize with AQP4 expression, most strongly for tau and TDP-43 proteinopathies, and high-atrophy regions lie close to AQP4 hotspots in anatomical and structural connectome space. Normative positron emission tomography markers of neuroinflammation strengthen the spatial alignment between AQP4 expression and disease atrophy. Last, we show that glioma is most frequent in AQP4-enriched regions. Collectively, this work highlights how AQP4 expression relates to brain physiology and vulnerability.