Glymphotherapeutics for Alzheimer’s disease: Time to move the needle

Alzheimer’s disease (AD), the most predominant neurodegenerative disease and a quintessential entity within the dementia umbrella, is a global public health crisis. While the lack of disease modifying therapies has been a weak point in AD treatment, the success of recently approved monoclonal antibody-based therapeutics (aducanumab and lecanemab) targeted at the removal of amyloid-beta (Aβ) peptides in the brain is still under debate. There are multiple safety concerns about these approved neurotherapeutics including amyloid-related imaging abnormalities, stroke, meningitis, encephalitis, and even death. Novel paradigms focused on aquaporin-4-mediated neuro-perivascular Aβ and Tau protein clearance pathway are garnering attention. In this paper, we argue that orchestrating the drug discovery focused on glymphatic clearance-facilitating drugs (“glymphotherapeutics”) might be a potentially novel and viable strategy to mitigate the progression and improve the clinical outcomes of AD. Current and experimental therapeutic approaches in Alzheimer’s disease: Cholinesterase inhibitors, Glutamate inhibitors, Anti-Ab immunotherapy, Glympho-therapeutics. • In the central nervous system, the glymphatic pathway represents an important neuro-perivascular clearance route. • Aquaporin-4 (AQP4) is a channel part of the glymphatic system, through which solutes like Aβ and tau are cleared from the brain. • AQP4 function decreases with aging and is significantly impaired in Alzheimer’s disease resulting in a reduction of solutes clearance. • Pharmacological interventions restoring AQP4 clearance function can offer a new therapeutic approach against Alzheimer’s disease.