Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer's disease

Abstract INTRODUCTION Although glymphatic function is involved in Alzheimer's disease (AD), its potential for predicting the pathological and clinical progression of AD and its sequential association with core AD biomarkers is poorly understood. METHODS Whole‐brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI‐ALPS) in participants with AD dementia ( n = 47), mild cognitive impairment (MCI; n = 137), and normal controls ( n = 235) from the Alzheimer's Disease Neuroimaging Initiative. RESULTS ALPS index was significantly lower in AD dementia than in MCI or controls. Lower ALPS index was significantly associated with faster changes in amyloid positron emission tomography (PET) burden and AD signature region of interest volume, higher risk of amyloid‐positive transition and clinical progression, and faster rates of amyloid‐ and neurodegeneration‐related cognitive decline. Furthermore, the associations of the ALPS index with cognitive decline were fully mediated by amyloid PET and brain atrophy. DISCUSSION Glymphatic failure may precede amyloid pathology, and predicts amyloid deposition, neurodegeneration, and clinical progression in AD. Highlights The analysis along the perivascular space (ALPS) index is reduced in patients with Alzheimer's disease (AD) dementia, prodromal AD, and preclinical AD. Lower ALPS index predicted accelerated amyloid beta (Aβ) positron emission tomography (PET) burden and Aβ‐positive transition. The decrease in the ALPS index occurs before cerebrospinal fluid Aβ42 reaches the positive threshold. ALPS index predicted brain atrophy, clinical progression, and cognitive decline. Aβ PET and brain atrophy mediated the link of ALPS index with cognitive decline.