Glymphatic Pathway Dysfunction in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis Using Diffusion...

To evaluate glymphatic dysfunction in mild cognitive impairment (MCI) using the diffusion tensor imaging along the perivascular space (DTI-ALPS) index.

Using PRISMA 2020, we searched PubMed, Web of Science, Scopus, and Embase (until May 10, 2025) for studies comparing the ALPS index in MCI patients versus healthy controls.

The pooled meta-analysis of 18 studies (1133 MCI patients, mean age 69.3 years; 1275 HCs) revealed a significantly lower ALPS index in MCI patients than in HCs (Cohen's d = -0.70; 95% CI: -1.10, -0.29; p < 0.001), with high heterogeneity (I² = 95.3%). Sensitivity analyses confirmed the robustness of the effect and a cumulative meta-analysis showed a consistent negative trend from 2021 to 2025. Subgroup analyses showed trends toward larger effect sizes in older patients (> 68 years, d = -0.83) and in studies using ≥ 64 diffusion directions (d = -0.99), although formal tests for subgroup differences were not statistically significant. Small-study effects were found (Egger's p = 0.004; Begg's p = 0.019), but the studies had high methodological quality. Trim-and-fill analysis added six studies, adjusting pooled Cohen's d from -0.70 to -0.98, indicating potential overestimation from publication bias.

These findings support the utility of the ALPS index as a noninvasive biomarker for early glymphatic dysfunction in cognitive decline.