Glymphatic dysfunction in Alzheimer's disease: a systematic review and meta-analysis of the DTI-ALPS index as an imaging biomarker.

INTRODUCTION

Although the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index is widely utilized as a proxy for glymphatic function in Alzheimer's Disease (AD) research, its association with core AD pathological biomarkers remains inconclusive due to inter-study heterogeneity. This systematic review aimed to investigate associations between the DTI-ALPS index and AD biomarkers and to elucidate potential sources of heterogeneity.

METHODS

The study protocol adhered to PRISMA guidelines and was registered with PROSPERO (CRD420251266067). We systematically searched Web of Science, PubMed, and ScienceDirect from January 1, 2017 to September 18, 2025 for studies examining the relationship between the DTI-ALPS index and core AD biomarkers. Random-effects meta-analyses were conducted when studies employed comparable methodologies and reported effect sizes while narrative synthesis was performed otherwise. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS) and the risk of bias was evaluated using the Risk of Bias in Systematic reviews (ROBIS) tool.

RESULTS

Thirty-six studies were included. Meta-analyses revealed significant correlations between the DTI-ALPS index (N = 22) and Aβ PET deposition (N = 9), MMSE (N = 15), and MoCA (N = 10) scores. Conversely, the association with tau PET deposition (N = 3) was not significant after adjusting for publication bias. Regarding clinical staging, indices were significantly lower in AD and mild cognitive impairment groups compared to controls but no difference was found between the two patient groups. Based on meta-regression and narrative synthesis results, we identified methodological variability and AD pathological complexity as primary sources of heterogeneity.

DISCUSSION: Consequently, we proposed the "GS Hub Integrative Framework." This framework posits that vascular, genetic, lifestyle, and environmental risk factors converge on glymphatic dysfunction (DTI-ALPS index) as a central hub, accelerating Aβ/tau accumulation, neurodegeneration, and cognitive decline. Future methodological standardization and refined patient stratification are essential for clinical translation.

SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251266067, identifier: CRD420251266067.