The study investigates the mechanism by which cerebrospinal fluid (CSF) facilitates the clearance of interstitial solutes, including amyloid β, from the brain parenchyma. Using in vivo two-photon imaging and radiolabeled tracers, the authors demonstrate that a significant portion of subarachnoid CSF cycles through the brain interstitial space via paravascular spaces surrounding penetrating arteries. Brain interstitial fluid is cleared along paravenous drainage pathways. Astrocytic aquaporin-4 (AQP4) is crucial for this process, as AQP4 knockout mice exhibit reduced CSF influx and a 70% decrease in interstitial solute clearance. The study also shows that fluorescent-tagged amyloid β, a peptide implicated in Alzheimer's disease, is transported along these paravascular pathways, and AQP4 deletion suppresses its clearance, suggesting that this pathway may remove amyloid β from the central nervous system. The findings highlight the importance of the paravascular pathway in maintaining brain homeostasis and its potential role in neurodegenerative diseases.The study investigates the mechanism by which cerebrospinal fluid (CSF) facilitates the clearance of interstitial solutes, including amyloid β, from the brain parenchyma. Using in vivo two-photon imaging and radiolabeled tracers, the authors demonstrate that a significant portion of subarachnoid CSF cycles through the brain interstitial space via paravascular spaces surrounding penetrating arteries. Brain interstitial fluid is cleared along paravenous drainage pathways. Astrocytic aquaporin-4 (AQP4) is crucial for this process, as AQP4 knockout mice exhibit reduced CSF influx and a 70% decrease in interstitial solute clearance. The study also shows that fluorescent-tagged amyloid β, a peptide implicated in Alzheimer's disease, is transported along these paravascular pathways, and AQP4 deletion suppresses its clearance, suggesting that this pathway may remove amyloid β from the central nervous system. The findings highlight the importance of the paravascular pathway in maintaining brain homeostasis and its potential role in neurodegenerative diseases.