Exploring the role of glymphatic system in Alzheimer's disease with insights from MRI-based studies: a systematic review

BACKGROUND: The glymphatic constitutes a crucial neurophysiological mechanism for the clearance of interstitial solutes and neurotoxic metabolites from the central nervous system. Dysfunction within this pathway is increasingly implicated in the etiopathogenesis of neurodegenerative diseases, notably Alzheimer's disease (AD). Advanced magnetic resonance imaging (MRI) modalities, such as diffusion tensor image analysis along the perivascular space (DTI-ALPS), have emerged as non-invasive, in vivo approaches quantifying glymphatic transport efficacy and its association with cognitive decline and AD progression. METHODS: This systematic review was conducted in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. and systematic literature retrieval was executed across PubMed, Cochrane, and Scopus databases, targeting studies that employed MRI-based metrics to assess glymphatic functionality in the context of AD. RESULTS: A total of 35 studies fulfilled the inclusion criteria. AD patients exhibited significantly reduced DTI-ALPS indices, correlating with elevated enlarged perivascular space (ePVS) volumes, neurocognitive deterioration, and cerebral atrophy. Notably ePVSs enlargement emerged as a surrogate marker of glymphatic dysfunction and a predictor of MCI-to-AD conversion. However, amyloid PET correlations exhibited inter-study heterogeneity. CONCLUSIONS: MRI derived biomarkers, particularly DTI-ALPS index and ePVSs analysis, demonstrate high potential as surrogate indicators of glymphatic impairment in AD. These findings underscore their diagnostic and prognostic value, warranting harmonization of imaging protocols and longitudinal investigations to establish their translational utility in clinical biomarker frameworks. CLINICAL RELEVANCE STATEMENT: MRI biomarkers of glymphatic dysfunction provide valuable insights into Alzheimer's disease pathophysiology and progression. These imaging markers may enhance early diagnosis, monitor disease progression, and evaluate treatment efficacy in AD.