Glymphatic System Dysfunction: The Missing Link Between Thyroid Functional Alterations and The Risk of Neurodegenerative Diseases

Background: Hypothyroidism, hyperthyroidism, thyroid eye disease (TED), and dysthyroid optic neuropathy (DON), are increasingly recognized for their neurological and cognitive consequences. The glymphatic system (GS), a brain-wide waste clearance pathway, has recently been implicated in the pathogenesis of several neurodegenerative diseases (NDs); however, its role in thyroid-related neurological impairment has not been systematically synthesized. Methods: A comprehensive literature search was performed across major electronic databases (MEDLINE, Web of Science, PubMed, Scopus, ScienceDirect, and Google Scholar), identifying and analyzing related studies on the topic.Results: Hypothyroidism (especially overt hypothyroidism), hyperthyroidism, and TED/NOD are associated with an increased risk of GS dysfunction and of NDs; among the mechanisms that explain this relationship are the disruption of AQP4 polarization and perivascular fluid dynamics, the accumulation of neurotoxic proteins (such as BA, α-synuclein, tau, among others), as well as the inflammatory response and the increase in venous congestion.Conclusion: Thyroid dysfunction (including TED/NOD) induces alterations in the functioning of the GS, which plausibly increases the risk of NDs. These findings suggest that thyroid function disorders should be taken into consideration in the pathogenesis of NDs.