Targeting glymphatic-associated pathways for Alzheimer’s disease: a review of non-invasive modulation strategies, mechanisms, and emerging evidence

Abstract

The glymphatic system, a cerebral waste clearance pathway identified over a decade ago, has reshaped understanding of Alzheimer’s disease (AD) pathogenesis by linking impaired brain homeostasis to amyloid-β and tau accumulation. This review synthesizes the biological mechanisms governing glymphatic function, including arterial pulsation, vasomotion, cerebrospinal fluid turnover, norepinephrine oscillations, aquaporin-4 polarization, and meningeal lymphatic drainage, and evaluates emerging non-invasive modulation strategies. Unlike immunotherapies that directly target pathological proteins with risks of amyloid-related imaging abnormalities, non-invasive approaches offer a new perspective, shifting from a target-and-eliminate strategy toward a restore-and-maintain strategy of endogenous clearance. A key insight is that therapeutic efficacy may depend more on engaging multiple mechanistic pathways concurrently than on the specific technology. Notably, preliminary evidence from small exploratory subgroup analyses suggests that APOEϵ4 carriers, despite exhibiting poorer baseline glymphatic function, may show differential responsiveness to certain non-invasive interventions, though these findings are hypothesis-generating and require independent replication in larger, prespecified trials. This review establishes a multidimensional evaluation framework spanning principles, mechanisms, and clinical evidence, providing theoretical support to accelerate translation of these promising strategies into AD therapeutics.