Glymphatic function associates with Alzheimer’s disease—signature region volumes, plasma biomarkers and white matter hyperintensity progression in cognitively unimpaired older adults

BACKGROUND: Brain glymphatic system is thought to play a critical role in the pathogenesis of Alzheimer's disease (AD). OBJECTIVE: To investigate the relationships between glymphatic function and AD-signature region volumes, plasma biomarkers and disease progression in cognitively unimpaired older adults. METHODS: Two datasets comprising a total of 229 cognitively unimpaired older adults were enrolled. Brain glymphatic function was assessed using diffusion tensor imaging along the perivascular space (DTI-ALPS). The associations between the DTI-ALPS index and volumes in AD-signature regions, including the basal forebrain, entorhinal cortex and hippocampus, were evaluated, along with white matter hyperintensity (WMH) volumes. In dataset 1 with plasma biomarkers, the mediation effects of DTI-ALPS index on plasma biomarkers and cognition were examined. In dataset 2 with follow-up data, the baseline DTI-ALPS index was correlated with the annual percent change in volumes of AD-signature regions and WMH. RESULTS: The DTI-ALPS index showed positive correlations with volumes in the basal forebrain, entorhinal cortex and hippocampus, and negative correlations with WMH volumes in both datasets. The DTI-ALPS index negatively associated with plasma phosphorylated tau (ptau) and mediated the relationship between ptau and cognition. The baseline DTI-ALPS index was negatively associated with WMH progression at follow-up. CONCLUSION: Worse glymphatic system function indicates decreased AD-signature region volumes, severe WMH lesions, elevated plasma ptau, and accelerated WMH progression before the occurrence of objective cognitive impairment. Therapeutic methods targeting the glymphatic system may prevent cognitive decline through the clearance of AD pathological proteins and the deceleration of WMH lesions.

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