Imaging biomarkers of glymphatic system dysfunction in Alzheimer's disease: a systematic review and meta-analysis...

Alzheimer's disease (AD) has been linked to impaired clearance of metabolic waste, and glymphatic dysfunction is increasingly considered a potential contributor to its pathogenesis. The diffusion tensor imaging-based analysis along the perivascular space (ALPS) index has been proposed as a non-invasive imaging marker, although findings across clinical studies remain inconsistent.

We systematically searched PubMed, Embase, Web of Science, Scopus, CENTRAL, and PEDro up to August 2025 in accordance with PRISMA guidelines. Studies reporting ALPS index values in adults with AD, mild cognitive impairment (MCI), or cognitively normal controls (NC) were included. Risk of bias was assessed using the AHRQ checklist, and the certainty of evidence was evaluated with GRADE.

Fifteen studies involving 1,756 participants were included in the meta-analysis. Pooled results showed a stepwise decrease in ALPS values, with significantly lower values in AD compared with NC (mean difference -0.20, I ² = 93%) and MCI (-0.09, I ² = 78%), as well as in MCI compared with NC (-0.11, I ² = 92%). Subgroup and sensitivity analyses supported the stability of these findings despite methodological heterogeneity.

The ALPS index shows a progressive decrease across the AD continuum, which is consistent with the presence of glymphatic alterations during disease progression. As a non-invasive MRI-derived marker, ALPS may have potential for use in early detection and monitoring; however, further validation with standardized imaging protocols and longitudinal studies is required before clinical application.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251119624, PROSPERO, CRD420251119624.