Background: The glymphatic system is intimately linked with the impaired clearance of abnormal proteins in Alzheimer’s disease (AD); however, direct evidence demonstrating this mechanism in humans is still limited. The potential of the glymphatic system to predict AD pathology, neurodegeneration, clinical progression, and conversion to Aβ positivity, as well as its sequential relationship with core biomarkers at different stages of AD, warrants further investigation.

Aim: Explore the relationship between glymphatic activity and the pathological features and clinical progress of AD.

Materials and Methods: A retrospective analysis of participants from the ADNI who underwent amyloid PET, MRI, and neuropsychological assessments. The study included individuals with AD (79.12 ± 8.66 years old; 17 males), mild cognitive impairment (MCI, 77.30 ± 7.98 years old; 12 males), and cognitively normal (CN, 78.22 ± 6.50 years old; 16 males) with a two-year follow-up. Whole-brain glymphatic activity measured by diffusion tensor imaging analysis along the perivascular space (DTI-ALPS).

Results: A faster decrease in the ALPS-index corresponds to a quicker Aβ deposition and a faster cognitive function decline (p=0.01). In the MCI-AD group, the accelerated turning point of the ALPS-index preceded Aβ deposition, while in the CN, MCI, and AD groups, it was later than Aβ deposition. The relationship between Aβ deposition and cognitive decline is fully mediated by the ALPS-index. A lower ALPS-index predicted higher Aβ burden and more severe cognitive decline (p<0.001), an increased risk of AD progression (HR = 2.5, 95%CI: 1.7, 3.7, p<0.001), and an increased risk of conversion to Aβ positivity (HR = 3.0, 95%CI: 1.6, 5.6, p<0.001).

Conclusion: Glymphatic dysfunction occurs prior to amyloid pathology and plays a pivotal role in Aβ deposition, heralding AD amyloid deposition, neurodegeneration, clinical progression, and conversion to Aβ positivity. The glymphatic system in the MCI stage exerts a protective effect on cognitive function in patients.

Keywords: Glymphatic system; Alzheimer’s disease; Mild cognitive impairment; DTI-ALPS; Cerebrospinal fluid biomarkers; Neurodegeneration