To the Editor:
I read with great interest the article recently published in Eye by Sen et al. . The authors nicely reviewed overlaps and missing links between Alzheimer’s disease (AD) and glaucoma, and concluded that several factors point toward a common pathogenesis at some level for both diseases. Since their publication, an entirely new ocular glymphatic clearance system has been discovered, which I believe may be a key missing piece of the AD-glaucoma puzzle.
The “glymphatic system” is a recently discovered cerebrospinal fluid (CSF) transport system that facilitates the clearance of neurotoxic molecules, including amyloid-β (Aβ), through a brain-wide network of perivascular pathways . Glymphatic dysfunction has been demonstrated in AD . The presence of a glymphatic pathway in the optic nerve (ON) and the hypothesis that a dysfunctional glymphatic system may be involved in the pathogenesis of glaucoma were first proposed in my paper published in 2015 . This hypothesis has been further supported by recent findings of impaired retrograde CSF inflow to the ON paravascular spaces in a mouse model of glaucoma .
In a follow-up paper , we also postulated the existence of an anterograde ocular glymphatic clearance system. We hypothesized that this could provide a route for the removal of toxic metabolites, such as Aβ, from the eye, and linked this pathway to glaucoma via disturbed glymphatic flow at the site of the lamina cribrosa . Now, a new study led by Nedergaard  confirmed this hypothesis-driven theory but also demonstrated that the ocular clearance path differs from the initial predictions. The authors identified a novel ocular glymphatic clearance route for fluid and wastes via the proximal ON in rodents. Aβ was cleared from the retina and vitreous via a pathway driven by the trans-lamina cribrosa pressure difference. After traversing the lamina barrier, intra-axonal Aβ was cleared via the perivenous space and subsequently drained to lymphatic vessels. Intriguingly, the authors further found that this ocular glymphatic pathway fails in glaucoma due to defects in the lamina barrier.
Considering the above, a novel link between AD and glaucoma could be the presence in both conditions of a dysfunction of the glymphatic system, as proposed in my original paper .
Sen S, Saxena R, Tripathi M, Vibha D, Dhiman R. Neurodegeneration in Alzheimer’s disease and glaucoma: overlaps and missing links. Eye. 2020. https://doi.org/10.1038/s41433-020-0836-x
Wostyn P, Van Dam D, Audenaert K, Killer HE, De Deyn PP, De Groot V. A new glaucoma hypothesis: a role of glymphatic system dysfunction. Fluids Barriers CNS. 2015;12:16.
Mathieu E, Gupta N, Paczka-Giorgi LA, Zhou X, Ahari A, Lani R, et al. Reduced cerebrospinal fluid inflow to the optic nerve in glaucoma. Investig Ophthalmol Vis Sci. 2018;59:5876–84.
Wostyn P, Killer HE, De Deyn PP. Glymphatic stasis at the site of the lamina cribrosa as a potential mechanism underlying open-angle glaucoma. Clin Exp Ophthalmol. 2017;45:539–47.
Wang X, Lou N, Eberhardt A, Yang Y, Kusk P, Xu Q, et al. An ocular glymphatic clearance system removes β-amyloid from the rodent eye. Sci Transl Med. 2020;12:eaaw3210.
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Wostyn, P. The “ocular glymphatic clearance system”: a key missing piece of the Alzheimer’s disease-glaucoma puzzle found?. Eye 35, 1281 (2021). https://doi.org/10.1038/s41433-020-1008-8