Cerebrospinal fluid outflow pathways in neurodegeneration: nasopharyngeal lymphatics and the ocular glymphatic-like axis.

The glymphatic system supports cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange and has been implicated, to different extents, in the transport or clearance of amyloid-β (Aβ), tau, lactate and other solutes. Although most studies have focused on CSF influx, astrocytic aquaporin 4 (AQP4) expression, perivascular localisation and polarisation, AQP4-mediated transmembrane water transport, and perivascular exchange, brain clearance also depends on efficient extracranial drainage of waste-containing fluid. In this narrative Review, we examine this 'outflow end', including meningeal lymphatic vessels, the cribriform plate-olfactory-nasal mucosal route, cranial perineural spaces, the nasopharyngeal lymphatic plexus, cervical lymphatic vessels and deep cervical lymph nodes. We highlight the skull base and nasopharyngeal lymphatic plexus as potential interfaces between intracranial CSF and extracranial lymphatic drainage and evaluate the route- and cargo-specific evidence for bulk-fluid and generic-tracer transport, soluble-protein clearance, aggregated-protein handling and immune-antigen drainage. We also consider experimental strategies targeting lymphatic contractility, VEGF-C-VEGFR3 signalling, mechanical stimulation, pressure gradients, AQP4-mediated transmembrane water transport and experimentally observed light-induced pupillary modulation. Throughout, we emphasise that evidence for individual cargoes, including Aβ, tau and α-synuclein, is uneven across anatomical routes and remains predominantly preclinical or indirect. Future studies integrating high-resolution lymphatic imaging, functional biomarkers and longitudinal or interventional designs are needed to determine whether altered CSF outflow is a consequence of neurodegeneration, a contributor to disease progression or a potentially modifiable process in neurodegenerative disease.