Investigating the DTI-ALPS index and its association with cognitive impairment in Alzheimer's disease: a diffusion...

With the global aging population, Alzheimer's disease (AD) poses a major health challenge. The diffusion tensor image (DTI) analysis along the perivascular space (DTI-ALPS) index has emerged as a noninvasive imaging marker that indirectly reflects glymphatic function. However, its alterations in AD and their associations with cognitive impairment remain incompletely understood. This study primarily aimed to investigate changes in the bilateral ALPS index in patients with AD and to evaluate their associations with cognitive, functional, and emotional measures. Secondary analyses further explored white matter microstructural alterations and their relationships with the ALPS index.

In total, 35 patients with AD and 21 cognitively normal healthy controls (HC) underwent 3.0T MRI and neuropsychological assessments. Tract-based spatial statistics (TBSS) analysis revealed areas of white matter damage and injured fibers in patients. Bilateral ALPS indices were compared between groups using analysis of covariance (ANCOVA) adjusted for age and gender. TBSS and ROI-based ANCOVA analyses of fractional anisotropy (FA) and mean kurtosis (MK) were performed as secondary analyses. Partial correlation analyses were used to examine associations between ALPS indices, white matter metrics, and neuropsychological scores.

Compared with the HC group, the AD group showed significantly lower bilateral ALPS indices, and these differences remained significant after adjustment for age and gender (left: F = 14.404, P < 0.001; right: F = 28.513, P < 0.001). Bilateral ALPS indices were significantly correlated with cognitive and functional measures, including the Mini-Mental State Examination, Montreal Cognitive Assessment, and Activities of Daily Living (ADL), and were also significantly associated with emotional measures, including the Hamilton Anxiety Scale and Hamilton Depression Scale. Among these, the strongest associations were observed with ADL (left: r = 0.688; right: r = 0.701; both P_FDR < 1 × 10-7). Secondary analyses revealed widespread white matter microstructural alterations in AD. Region-of-interest-based analyses showed that the left hippocampal cingulum exhibited significant differences in both FA and MK, and these metrics were positively associated with the ALPS index as well as with cognitive and functional performance.

The glymphatic system of AD patients has a reduced ability to clear waste. The ALPS index was closely associated with cognitive, functional, and emotional status, while white matter abnormalities, particularly in the left hippocampal cingulum, may represent a structural correlate of glymphatic dysfunction in AD.