Diffusion Tensor Imaging Along the Perivascular Space (DTI-ALPS) as a Neuroimaging Biomarker of Glymphatic Function in Neurodegenerative Diseases: A Systematic Review

The glymphatic system has been proposed as a brain-wide pathway that promotes the exchange between cerebrospinal and interstitial fluids and facilitates the clearance of metabolic waste products, including amyloid-β and tau proteins. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) has emerged as a non-invasive magnetic resonance imaging technique proposed to indirectly assess glymphatic-related fluid dynamics. This systematic review evaluated the methodological consistency and clinical applicability of the ALPS index in neurodegenerative diseases. A structured search of PubMed (MEDLINE) and Web of Science identified human studies published up to January 2026 investigating DTI-ALPS in neurodegenerative conditions. Data regarding study populations, MRI acquisition parameters, image-processing methods, statistical approaches, and clinical associations were extracted and synthesized. Ten studies met the inclusion criteria. Across studies, lower ALPS index values were generally associated with cognitive impairment, amyloid burden, and disease severity, particularly in Alzheimer's disease. Several studies incorporated multimodal biomarkers, including amyloid positron emission tomography and cerebrospinal fluid markers, thereby improving the biological interpretation of DTI-ALPS findings. However, substantial methodological heterogeneity was identified across studies, including variability in region-of-interest placement, diffusion acquisition protocols, and image-processing pipelines. Furthermore, the interpretation of diffusivity metrics as direct measures of glymphatic flow remains controversial. Current evidence suggests that DTI-ALPS may represent a promising non-invasive imaging marker of glymphatic-related alterations; however, its biological specificity and clinical applicability remain insufficiently established. Standardized acquisition protocols, harmonized analytical pipelines, and longitudinal multicenter studies are required to clarify its role in neurodegenerative disease research.