The glymphatic system is an essential fluid-clearance system in brain, and has been suggested as a potential therapeutic target for Alzheimer’s disease (AD). However, its potential for tracking the pathological and clinical progression of AD and its sequential association with core AD biomarkers in human brain is poorly understood.

We aimed to investigate the cross-sectional and longitudinal associations between glymphatic activity indicated by the diffusion tensor image analysis along the perivascular space (DTI-ALPS) and clinical and pathological features of AD.

Whole-brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS) in participants with AD (n=47), mild cognitive impairment (n=137), and normal controls (n=235) from the Alzheimer’s Disease Neuroimaging Initiative.

Decreased ALPS-index was observed in AD dementia, prodromal AD, and preclinical AD patients. At baseline, the ALPS-index was significantly correlated with amyloid biomarkers (i.e., CSF Aβ42 and AV45 PET), neuroimaging markers of neurodegeneration (i.e., FDG PET SUVR, residual hippocampal volume, and residual AD-signature ROI volume), and AV1451 PET. Longitudinally, lower ALPS-index was significantly associated with faster changes in amyloid PET burden (AV45 PET) and AD-signature ROI volume, higher risk of amyloid-positive transition and clinical progression, and faster rates of amyloid- and neurodegeneration-related cognitive decline. Furthermore, the associations of ALPS-index with cognitive decline were fully mediated by amyloid PET and brain atrophy.