Yi‐Chia Wei, W-H Huang, Chemin Lin, Chemin Lin, Chih-Ken Chen, Chih-Chin Heather Hsu, Chao-Hsin Michael Ding, Yao-Liang Chen, Ching-Po Lin, Ching-Po Lin
BackgroundGlymphatic system dysfunction is linked to cognitive decline in dementia continuum. Diffusion magnetic resonance imaging markers like the Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS) index and whole-brain free water (FW) fraction allow non-invasive evaluation of glymphatic activity.ObjectiveThis study assessed whether DTI-ALPS and FW fraction are associated with cognitive performance and examined the influence of factors such as education on these relationships across dementia stages.MethodsCognitively normal, mild cognitive impairment, and dementia participants were recruited from both the community and the memory clinic at Chang Gung Memorial Hospital, Keelung. Brain MRI and neuropsychological assessments were performed.ResultsA total of 127 individuals (Clinical Dementia Rating 0, 0.5, 1-3; N = 75, 43, 6) completed the study. Both DTI-ALPS index and FW fraction differed among groups (p < 0.001) and correlated with cognitive performance (DTI-ALPS: β = 0.35; FW: β = -0.50; both p < 0.001). Mediation analysis showed that DTI-ALPS was positively associated with Montreal Cognitive Assessment (total effect b = 21.94, p < 0.001), largely mediated by FW fraction (indirect β = 0.22, 95% CI [0.14-0.33]). After adjusting for age, sex, and education, the total effect remained significant (b = 10.93, p = 0.018), while the direct effect was not (b = 8.15, p = 0.080), and the indirect effect via FW persisted (β = 0.05, 95% CI [0.01-0.13]). Education moderated these associations (DTI-ALPS x education: b = -2.07, p = 0.033; FW x education: b = 5.59, p = 0.034). In addition, sleep-medication use interacted with FW fraction in relation to cognitive performance (FW x sleep-medication: b = -58.87, p = 0.044).ConclusionsDTI-ALPS index and FW fraction provided complementary insights into glymphatic dysfunction linked to cognitive decline. Higher DTI-ALPS values were associated with better cognition, mediated by lower whole-brain FW, but with attenuated effects in individuals with higher education.