Unlocking the enigma: unraveling multiple cognitive dysfunction linked to glymphatic impairment in early Alzheimer’s disease

Abstract

BackgroundAlzheimer’s disease (AD) is one of the world’s well-known neurodegenerative diseases, which is related to the balance mechanism of production and clearance of two proteins (amyloid-β and tau) regulated by the glymphatic system. Latest studies have found that AD patients exhibit impairments to their glymphatic system. However, the alterations in the AD disease continuum, especially in the early stages, remain unclear. Moreover, the relationship between the glymphatic system and cognitive dysfunction is still worth exploring.MethodsA novel diffusion tensor image analysis method was applied to evaluate the activity of the glymphatic system by an index for diffusivity along the perivascular space (ALPS-index). Based on this method, the activity of the glymphatic system was noninvasively evaluated in 300 subjects, including 111 normal controls (NC), 120 subjects with mild cognitive impairment (MCI), and 69 subjects with AD. Partial correlation analysis was applied to explore the association between glymphatic system and cognitive impairment based on three domain-general scales and several domain-specific cognitive scales. Receiver operating characteristic curve analysis was used to evaluate the classification performance of ALPS-index along the AD continuum.ResultsALPS-index was significantly different among NC, MCI and AD groups, and ALPS-index decreased with cognitive decline. In addition, ALPS-index was significantly correlated with the scores of the clinical scales (p<0.05, FDR corrected), especially in left hemisphere. Furthermore, combination of ALPS and fractional anisotropy (FA) values achieved better classification results (NC vs. MCI: AUC = 0.6610, NC vs. AD: AUC = 0.8214).ConclusionHere, we show that the glymphatic system is closely associated with multiple cognitive dysfunctions, and ALPS-index can be used as a biomarker for alterations along the AD continuum. This may provide new targets and strategies for the treatment of AD, and has the potential to assist clinical diagnosis.