International journal of molecular sciencesOct 27, 2026

The Brain’s Waste Clearance and Cell Recycling Systems in ME/CFS and Long COVID: Possible Mechanisms

Long Covid Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 28, 2026

Abstract

60-400 million individuals globally are affected by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID.

ME/CFS and Long COVID are complex multisystem disorders characterized by overlapping symptoms and biological mechanisms.
Common symptoms include persistent fatigue, sleep dysfunction, post-exertional malaise, and cognitive difficulties.
Both conditions are considered post-infectious illnesses, with immune dysregulation and orthostatic intolerance as key features.
Glymphatic dysfunction and impaired autophagy may play significant roles in the pathophysiology of these disorders.
The interaction between the glymphatic and meningeal lymphatic systems may be essential for brain waste removal and homeostasis.

Simplified

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Post-Acute Sequelae of SARS-CoV-2 infection (Long COVID) are complex multisystem disorders affecting 60-400 million individuals globally. They are considered post-infectious illnesses and share similar biological mechanisms, including immune dysregulation, orthostatic intolerance and cognitive dysfunction, highlighting a substantial overlap between the two conditions. Persistent fatigue, sleep dysfunction, post-exertional malaise and brain fog are among some of their most common and debilitating symptoms. Despite extensive research, they remain incurable, with no effective treatments, or simple diagnostic tests. They are increasingly understood as heterogeneous, multisystem diseases, involving neurological symptoms, with varying severities and diverse underlying biological abnormalities. More recently, the possibility of glymphatic dysfunction and autophagy impairment have been proposed as parts of the mechanistic features of the pathophysiology of these conditions, which are discussed more fully in the present perspective. With the glymphatic and meningeal lymphatic systems being operationally integrated, we will try to delineate how the metabolic waste removal mechanism afforded by this system may work together with autophagy to maintain brain homeostasis. We will provide some of the established mechanistic features of toxicity of misfolded proteins, explore their role in causing glymphatic dysfunction and impairing autophagy, and discuss the potential for therapeutic interventions.

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The Brain’s Waste Clearance and Cell Recycling Systems in ME/CFS and Long COVID: Possible Mechanisms

Abstract

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