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The glymphatic system is one of the pathways for drainage of cerebrospinal fluid from the brain to the body. This drainage is necessary to remove metabolic waste from the brain, and there is good evidence for reduced outflow of cerebrospinal fluid to lead to the development of neurodegenerative conditions. The work here adds to this body of evidence, showing that impaired flow of cerebrospinal fluid through the glymphatic system correlates with later severity of Alzheimer’s disease.
The glymphatic system is an essential fluid-clearance system in the brain. The highly organized cerebrospinal fluid (CSF) transport system subserves the influx of CSF into the brain parenchyma along the arterial perivascular spaces and subsequent transfer to the brain interstitial space. Impaired brain clearance mechanisms may be an essential factor contributing to the deposition of pathological proteins in Alzheimer’s disease (AD). The novel fluid transport system provides a promising target for the prevention or treatment of AD.
Recently, a measure of perivascular clearance activity in the human brain using diffusion MRI called diffusion tensor image analysis along the perivascular space (DTI-ALPS) has been proposed. The reliability of the ALPS index as a measure of glymphatic activity was supported in a recent study that found a significant correlation between the ALPS index and glymphatic clearance function. In the field of AD, previous studies have observed a decreased ALPS index in AD patients compared to controls. The ALPS index is also associated with cognitive performance in AD and is negatively associated with amyloid and tau deposition on positron emission tomography (PET) images.
In the present study, we used the ALPS index to investigate the cross-sectional and longitudinal associations between glymphatic activity and clinical and pathological features of AD, including diagnosis, cognitive scores, and CSF and neuroimaging biomarkers. Taking advantage of the large-scale and longitudinal measurements of the ALPS index and AD hallmarks in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, we further investigated the sequential relationship between glymphatic dysfunction, as measured by the ALPS index, and markers of AD pathology in the development of AD.
ALPS index was significantly lower in AD dementia than in mild cognitive impairment (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. Thus glymphatic failure may precede amyloid pathology, and predicts amyloid deposition, neurodegeneration, and clinical progression in AD.