Glymphatic system health in early Alzheimer’s disease and its relationship to sleep, cognition and CSF biomarkers

Abstract BACKGROUND The glymphatic system is thought to facilitate waste clearance from the brain during sleep. Impairment in this system may underpin the elevated deposition of pathological proteins in neurodegenerative conditions like Alzheimer’s disease (AD). Putative glymphatic system activity has been measured with contrast-enhanced, serial MRI, revealing slower clearance in people who are sleep deprived. It is important that these methods are used to understand changes to glymphatic function in people with early-stage AD. METHODS Twenty-four individuals with mild cognitive impairment were recruited. N=20 had CSF biomarker data, with 16 meeting criteria for AD positivity (AD+). Participants underwent polysomnography, cognitive testing and serial T1 MRI with intravenous gadolinium-based contrast agent, diffusion tensor imaging along the perivascular space (DTI-ALPS index), and core AD CSF biomarkers collection. Rate (over 24hrs) and efficiency (the amount of tracer cleared after 28hrs relative to uptake after 4hrs) of GCBA clearance were measured. RESULTS Faster/more efficient GBCA clearance was associated with shorter sleep latency. In AD+ participants faster 24hr clearance of GBCA was associated with a lower ratio of Aβ1–42/Aβ1–40 in the CSF. In addition, better clearance efficiency was associated with greater levels of Aβ1-40, lower levels of Aβ-1-42, and a smaller ratio of Aβ1–42/Aβ1–40 in the CSF. Higher DTI-ALPS indicated better cognitive performance and, unexpectedly, higher tau levels. However, it was not associated with GCBA clearance. CONCLUSIONS We show, for the first time in humans, that glymphatic system function is associated with AD-related changes to sleep, cognition and core AD biomarker concentrations in CSF. However, for AD biomaker concentrations, these relationships are not in the expected direction: higher concentrations and lower Aβ1–42/Aβ1–40 ratio were associated with faster or more efficient clearance of GCBA. We suggest that increased neurodegeneration in those with elevated levels of tau and Aβ1–40 may paradoxically increase glymphatic activity locally to brain regions with more atrophy relative to less, but not in a way that improves sleep or cognition. In fact, larger extracellular spaces may exacerbate the spread of tau via the glymphatic system and therefore accelerate the progression of AD.