Objective: The glymphatic system cleans amyloid and tau proteins from the brain in animal studies of Alzheimer disease (AD). However, there is no direct evidence showing this in humans. Methods: Participants (n = 50, 62.6 AE 5.4 years old, 36 women) with AD and normal controls underwent amyloid positron emission tomography (PET), tau PET, structural T1-weighted magnetic resonance imaging, and neuropsychological evaluation. Whole-brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS). Results: ALPS-indexes showed negative correlations with deposition of amyloid and tau on PET images and positive correlations with cognitive scores even after adjusting for age, sex, years of education, and APOE4 genotype covariates in multiple AD-related brain regions (all p < 0.05). Mediation analysis showed that ALPS-index acted as a significant mediator between regional standardized uptake value ratios of amyloid and tau images and cognitive dysfunction even after correcting for multiple covariates in AD-related brain regions. These regions are responsible for attention, memory, and executive function, which are vulnerable to sleep deprivation. Interpretation: Glymphatic system activity may act as a significant mediator in AD-related cognitive dysfunction even after adjusting for multiple covariates and gray matter volumes. ALPS-index may provide useful disease progression or treatment biomarkers for patients with AD as an indicator of modulation of glymphatic activity.

Background and Objectives:The glymphatic system, which is robustly enabled during some stages of sleep, is a fluid-transport pathway that clears cerebral waste products. Most contemporary knowledge regarding glymphatic system is inferred from rodent experiments and human research is limited. The objective of the research is to explore the associations between human glymphatic function, sleep, neuropsychological performances, and cerebral gray matter volumes.Methods:This cross-sectional study included individuals 60 years or older who had participated in the Integrating Systemic Data of Geriatric Medicine to Explore the Solution for Health Aging study between September 2019 and October 2020. Community-dwelling older adults were enrolled at 2 different sites. Participants with dementia, major depressive disorders, and other major organ system abnormalities were excluded. Sleep profile was accessed using questionnaires and polysomnography. Administered neuropsychological test batteries included Everyday Cognition (ECog) and the Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Battery (CERAD-NB). Gray matter volumes were estimated based on magnetic resonance imaging (MRI). Diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS) index was used as the MRI marker of glymphatic function.Results:A total of 84 participants (mean [SD] age, 73.3 [7.1] years, 47 [56.0%] women) were analyzed. Multivariate linear regression model determined that age (unstandardized β, -0.0025 [SE, 0.0001]; P = 0.02), N2 sleep duration (unstandardized β, 0.0002 [SE, 0.0001]; P = 0.04), and the apnea-hypopnea index (unstandardized β, -0.0011 [SE, 0.0005]; P = 0.03) were independently associated with DTI-ALPS. Higher DTI-ALPS was associated with better ECog language scores (unstandardized β, -0.59 [SE, 0.28]; P = 0.04) and better CERAD-NB word-list-learning delayed recall subtest scores (unstandardized β, 6.17 [SE, 2.31]; P = 0.009) after co-varying for age and education. Higher DTI-ALPS was also associated with higher gray matter volume (unstandardized β, 107.00 [SE, 43.65]; P = 0.02) after controlling for age, gender, and total intracranial volume.Discussion:Significant associations were identified between glymphatic function and sleep stressing the importance of sleep for brain health. This study also revealed associations between DTI-ALPS, neuropsychological performances, and cerebral gray matter volumes suggesting the potential of DTI-ALPS as a biomarker for cognitive disorders.