Abstract:
Background: Alzheimer’s disease (AD) and Parkinson’s disease (PD) are progressive neurodegenerative disorders that share the accumulation of toxic proteins as a pathological hallmark, with AD primarily associated with amyloid β (Aβ) and tau, and PD with α-synuclein. Growing evidence suggests impaired glymphatic function may contribute to the accumulation of these proteins, disrupt brain homeostasis, and lead to disease progression in both disorders. Aquaporin-4 (AQP4), a water channel localized at the astrocytic endfeet, contributes to glymphatic clearance. Disruption of this localization, referred as AQP4 depolarization, has been associated with impaired glymphatic clearance, protein accumulation and neuroinflammation. AQP4 depolarization may represent a shared mechanism linking glymphatic dysfunction to neurodegeneration, yet its potential as a modifiable therapeutic target and a reliable measurement in humans remain unresolved.
Objective: To synthesize mechanistic and human evidence supporting AQP4 polarisation as a shared glymphatic bottleneck in AD and PD and evaluate its biomarker and therapeutic potential for translation.
Methods: A PRISMA-guided literature review was conducted using PubMed, Scopus, and Google Scholar. Studies were screened using predefined eligibility criteria. Extracted data were analysed and visualised using R (ggplot2) in Google Collab. Studies were excluded if they were duplicates, non-English, bibliometric analyses, unrelated to AD/PD glymphatic physiology or studies lacking AQP4 polarization/glymphatic outcomes.
Results: Mechanistic evidence linked AQP4 depolarization with impaired glymphatic clearance, where amyloid β (Aβ) and tau accumulation was associated with AD, while α-synuclein accumulation was associated with PD. Diffusion Tensor Imaging-Analysis Along the Perivascular Space (DTI-ALPS) indices were evaluated across AD, mild cognitive impairment (MCI), subjective cognitive decline (SCD), and early PD groups. This index decreased from 1.51 ± 0.08 in SCD (n=6) to 1.37 ± 0.13 in MCI (n=35) and 1.32 ± 0.14 in AD (n=99) with statistically significant results (p=0.001). In early PD, DTI-ALPS was statistically significantly reduced compared to health adults (1.41 ± 0.13 vs 1.62 ± 0.42, p<0.001). These findings supported impaired glymphatic function in both diseases. Preclinical PERK inhibition restored AQP4 polarization and improved glymphatic clearance, suggesting therapeutic potential.
Conclusion:AQP4 endfoot polarization may represent a convergent mechanism linking ageing, vascular dysfunction, and neuroinflammation to impaired glymphatic clearance in AD and PD, contributing to protein accumulation. While DTI-ALPS is a promising biomarker for assessing glymphatic dysfunction, evidence supporting AQP4 as a convergent ‘bottleneck’ remains limited because of differences between experimental and human studies. Preclinical evidence, like PERK inhibition, suggests therapeutic potential in possibly restoring AQP4 polarization, however the findings do require validation in humans before translation.
Biography:
Fatima Zubair is from the United Kingdom, currently a fifth-year medical student at Georgian American University in Tbilisi, Georgia, with research interests in neuroscience, surgery, and emergency medicine.
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