The biomechanical Breakdown of the Glymphatic System in Early-Onset Alzheimer’s Disease: A Systematic Review
DOI:
https://doi.org/10.58445/rars.3908Keywords:
Aquaporin-4, Early-Onset Alzheimer's Disease, Glymphatic System, N3 Sleep, ProteostasisAbstract
This systematic review focuses on the biomechanical and molecular breakdown of the glymphatic system in Early-Onset Alzheimer’s Disease. In contrast to past studies focusing on amyloid-beta overproduction, new perspectives suggest the disorder is caused by the functional failure of the brain’s innate clearance system. The transition into the non-rapid eye movement (NREM) phase acts as a mechanical trigger that expands the extracellular space, allowing cerebrospinal fluid to drive out neurotoxic waste through Aquaporin-4 (AQP4). Furthermore, the Intramural Periarterial Drainage (IPAD) pathway harnesses the rhythmic pulsations of arterial blood vessels to pump and clear toxic metabolic waste. A novel "Two-Hit" hypothesis suggests that when inherent genetic vulnerability combines with disrupted sleep architecture, it creates a continuous positive feedback loop of toxic protein accumulation and vascular damage. Findings underscore the need to incorporate polysomnography and neuroimaging biomarkers (like the DTI-ALPS index) into longitudinal research to develop preventative treatments aimed to restore hydrodynamic balance within the brain.
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