Glymphatic System Dysfunction in Alzheimer's Disease: Insights into its Mechanisms, Diagnostic Imaging, and Therapeutic Perspectives: A Systematic Review.
Level 5 - mechanism / opinion, no new human data
Systematic review synthesizing predominantly preclinical animal models and observational human neuroimaging studies.
PubMed 41928632 · doi:10.2174/0115672050428286260225033532
What was done
A systematic review was conducted across PubMed, Scopus, and Web of Science up to June 2025 to examine glymphatic system dysfunction in Alzheimer's disease (AD). Thirteen studies were included (noted as 5 preclinical experiments, 8 human imaging or biomarker studies, and 1 clinical trial protocol) evaluating amyloid-β and tau clearance, neuroimaging markers (such as DTI-ALPS, perivascular spaces, and PET), cognitive metrics, and therapeutic modulations.
What was found
The abstract provides qualitative directions without numerical effect sizes or statistics. Preclinical studies demonstrated that reduced aquaporin-4 (AQP4) polarization and impaired CSF-interstitial fluid exchange enhance amyloid-β deposition and plaque formation. Human neuroimaging studies linked reduced glymphatic function (via DTI-ALPS) in mild cognitive impairment and AD to higher amyloid burden, worse cognitive outcomes, and disrupted sleep. Preclinical interventions (aerobic exercise, 40 Hz gamma sensory stimulation) improved glymphatic clearance and reduced amyloid levels.
Why it matters
This synthesis connects translational clearance mechanisms with human neuroimaging markers, highlighting the glymphatic pathway as a potential biomarker source and therapeutic target for AD pathology.
Limits
The abstract provides no quantitative data, odds ratios, or effect estimates. The underlying evidence base is small and heavily dependent on preclinical models and cross-sectional human imaging, precluding definitive causal conclusions. Human interventional evidence is nascent, with key therapeutic studies remaining in the protocol stage.
Cited by
- supports Impairing glymphatic clearance through sleep disruption or aquaporin-4 disruption increases the accumulation of amyloid plaques and inflammatory cytokines like interleukins and TNF-alpha in the brain.