Abstract
PURPOSE: Impaired glymphatic function is considered an important characteristic of cognitive decline, but the role of tau pathology as a mediator remains unclear. This study investigated whether tau burden mediates the association between diffusion tensor image analysis along the perivascular space (DTI-ALPS) and cognitive impairment or brain atrophy. Also, we explored whether DTI-ALPS index predicts longitudinal cognitive deterioration over time. METHODS: We included 144 individuals with mild cognitive impairment (MCI), Alzheimer's disease dementia (ADD), and other dementia, or normal cognition. All participants underwent 3.0-Tesla MRI, (18)F-MK6240 and (18)F-Flutemetamol PET scans, APOE genotyping, and comprehensive neuropsychological assessments. Among these, 101 were followed longitudinally for two years. Mediation analyses within a causal framework were used to investigate whether tau burden mediated the association between DTI-ALPS index and cognition function and structural MRI measures. Longitudinal associations were tested using linear mixed-effects models. RESULTS: DTI-ALPS index was significantly lower in cognitively impaired individuals compared to cognitively normal (CN) participants. Lower DTI-ALPS index was associated with higher tau burden and worse cognitive function. Tau burden was also inversely associated with cognition. Mediation analysis indicated that tau burden accounted for approximately 21-27% of the association between DTI-ALPS and cognition. Longitudinal analysis showed baseline lower DTI-ALPS index also predicted faster longitudinal cognitive decline. CONCLUSION: Our findings suggest that the DTI-ALPS index is an indirect marker of glymphatic dysfunction associated with tau accumulation and cognitive decline. Tau pathology may partially link compromised glymphatic clearance to cognitive impairment.