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.