Modulating glymphatic clearance in Alzheimer's disease: Molecular mechanisms, imaging biomarkers, and emerging interventions - PubMed
4 hours ago
- #Neuroimaging biomarkers
- #Glymphatic system
- #Alzheimer’s disease
- The glymphatic system facilitates cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange, aiding in the clearance of neurotoxic proteins like amyloid beta (Aβ) and tau.
- Glymphatic dysfunction is linked to Alzheimer's disease (AD), though causality in humans is not fully established.
- Loss of aquaporin 4 (AQP4) polarization at astrocytic endfeet is associated with reduced CSF-ISF exchange and increased Aβ and tau burden.
- Other contributors to glymphatic dysfunction include meningeal lymphatic impairment, blood-brain barrier disruption, altered vascular pulsatility, sleep fragmentation, and perivascular structural remodeling.
- Clinical measures like perivascular space (PVS) enlargement and diffusion tensor-based indices (e.g., ALPS index) provide indirect readouts of perivascular fluid behavior but have limitations.
- Contrast-enhanced MRI can more directly probe clearance but is invasive and not scalable for routine use.
- Fluid biomarkers, such as CSF AQP4 and related transport proteins, show promise but need validation in large multicenter cohorts.
- Therapeutic approaches include sleep and circadian optimization, vascular risk control, aerobic exercise, neuromodulation (e.g., gamma frequency sensory stimulation), and molecular strategies targeting AQP4 anchoring.
- Standardized biomarkers and longitudinal interventional trials are needed to assess the impact of improving clearance proxies on AD biomarkers and clinical outcomes.