The DTI analysis along the perivascular space (DTI-ALPS) index is widely used to assess water diffusion alterations in Alzheimer's disease (AD), yet its biological interpretation remains debated. We investigated DTI-ALPS associations with regional amyloid-β (Aβ) deposition, glucose metabolism, and cognitive function in Chinese patients with AD and mild cognitive impairment (MCI), offering finer-grained imaging evidence for its pathophysiological interpretation.

34 AD dementia (ADD) patients, 40 MCI patients, and 52 cognitively normal controls (NCs) underwent MRI, ¹⁸ F-florbetapir ( ¹⁸ F-AV45) (standardized uptake value ratio, SUVR; centiloid values, CL), and ¹⁸ F-FDG (SUVR) imaging. MRI volumetry and PET quantification used Neurophet SCALE PET software. Mediation analysis tested ALPS effects between pathology/metabolism and cognition.

ALPS differed significantly across groups (ADD:1.152 ± 0.113; MCI:1.247 ± 0.122; NC:1.302 ± 0.121; p < 0.001). Adjusted for age, sex, education, and APOE4, ALPS correlated positively with MMSE (r = 0.324, p < 0.001) and MoCA (r = 0.311, p < 0.001) and negatively with CL (r=-0.415, p < 0.001). The ALPS index showed negative correlations with ¹⁸ F-AV45 PET SUVR in nearly all brain regions, with the strongest negative associations observed in the posterior cingulate (r=-0.459), paracentral (r=-0.445), superior frontal (r=-0.441), and inferior temporal (r=-0.433) regions. For ¹⁸ F-FDG PET SUVR, the ALPS index demonstrated bidirectional correlations: positive in regions including the inferior parietal (r = 0.396), isthmus of cingulate (r = 0.376), and precuneus (r = 0.369), but negative in the paracentral (r=-0.418), precentral (r=-0.406), and cerebellar white matter (r=-0.374) (all p < 0.001). Mediation analysis revealed that the ALPS index mediates the relationships between glucose metabolism/Aβ accumulation and both abstract thinking and memory. Parietal/cingulate isthmus/precuneus FDG metabolism showed significant ALPS-mediated indirect effects across cognitive domains ( p < 0.05).

The ALPS index correlates with Aβ deposition and exhibits region-specific metabolic associations in AD, mediating amyloid-metabolism-cognition pathways and predicting cognitive decline. These findings provide a region-wise correlation map of perivascular water diffusion alterations in AD, informing future research directions, though underlying mechanisms require validation.