Gray matter atrophy mediated the association between glymphatic function and cognition in Alzheimer’s disease: a multicenter DTI-ALPS study

Although emerging evidence links glymphatic dysfunction to Alzheimer’s disease (AD), whether this association depends on structural brain changes remains unknown. In this study, we employed Diffusion Tensor Imaging Analysis along the Perivascular Space (DTI-ALPS) to assess the glymphatic alterations along the AD continuum in a Chinese cohort and explored whether these alterations are statistically mediated by gray matter (GM) or white matter (WM) atrophy as anchored by the ALPS-index. We assessed glymphatic function using the ALPS-index in 200 participants with normal controls (NC, n = 72), mild cognitive impairment (MCI, n = 52), and AD dementia (n = 76) from three hospitals. Data were harmonized using ComBat to correct batch effects. Group differences in ALPS-index, gray matter volume fraction (GMVF), and white matter volume fraction (WMVF) were analyzed via ANOVA. Correlations among the DTI-ALPS index, GMVF/WMVF, and cognitive/functional outcomes were analyzed. Multivariate ANOVA assessed regional GM/WM differences. Multiple regression identified brain regions anchored to ALPS-index. Mediation analyses tested whether GMVF, WMVF, or GM/WM regions statistically mediated the relationship between ALPS-index and outcomes. The ALPS-index demonstrated progressive decline across groups (NC:1.45 ± 0.13; MCI:1.33 ± 0.14; AD:1.22 ± 0.13; F = 19.80, p < 0.001), with medium-to-large effect sizes (d = 0.48–0.82). The ALPS-index was correlated with the mini mental state examinations (MMSE) (β = 0.292, p (FDR) = 0.002), montreal cognitive assessment (MoCA) (β = 0.307, p (FDR) = 0.002) and activity of daily living scale (ADL) (β = -0.210, p (FDR) = 0.020). Both the GMVF and WMVF, as well as the regional alterations in GM and WM, showed statistically significant differences between the AD and NC groups, whereas no significant alterations were observed in the MCI group. GMVF, WMVF, left hippocampus and right parahippocampal gyrus mediated the relationship between the ALPS-index and cognitive function/functional status. Our findings demonstrate progressive glymphatic dysfunction across the AD continuum. GMVF and specific GM regions were statistically associated with the relationship between glymphatic function and cognitive function/functional status, indicating an indirect association between glymphatic impairment and AD progression via GM degeneration. These results support glymphatic function associated structural degeneration as potential tools for AD monitoring and highlight GM preservation as a therapeutic target.