Poor glymphatic function is associated with mild cognitive impairment and its progression to Alzheimer's disease: A DTI-ALPS study

We aimed to explore the association between ALPS index and both risks of MCI from cognitively normal (CN) and incident AD progressed from MCI, as well as potential mediating factors. This study included 519 adults including 253 (48.75 %) CN and 266 (51.25 %) MCI participants from Alzheimer's Disease Neuroimaging Initiative. Glymphatic function (assessed by along the perivascular space [ALPS] index) was measured by diffusion tensor image at baseline. Neurobiomarkers (Aβ and tau from CSF, plasma and PET) and cognitive functions were served as mediators. Data were analyzed using Cox and Laplace regression and mediation analysis. During follow-up (median 3.6 years, interquartile range [IQR]: 2.0-4.9 years), 30 (11.86 %) participants developed MCI in the CN cohort and 73 (27.4 %) participants progressed to AD in the MCI cohort. The hazard ratios (95 % confidence intervals [CIs]) of the higher ALPS index was 0.605 (0.386-0.948) for MCI and 0.501 (0.356-0.706) for AD. In addition, participants with high ALPS index had 3.837 and 3.466 years prolonged onset of MCI and AD, separately. Aβ in choroid plexus (17.1 %), tau in cortex [Inferiortemporal (21.1 %), Middletemporal (AV1451:17.0 %, FTP:15.5 %), Superiortemporal(7.7 %), Meta_temporal (AV1451:17.5 %, FTP:16.6 %)], and executive function (14.1 %) mediated the association between ALPS and MCI-AD progression. High ALPS index decreases MCI risk and delays MCI progression to AD by approximately 3.5 years. Aβ in choroid plexus, tau in cortex, and executive function may partially mediate the MCI-AD progression in relation to ALPS index.