Glymphatic function decline as a mediator of core memory-related brain structures atrophy in aging

Abstract Background and Objectives This study aimed to elucidate the role of the glymphatic system—a crucial pathway for clearing waste in the brain—in the aging process and its contribution to cognitive decline. We specifically focused on the diffusion tensor imaging analysis along the perivascular space (ALPS) index as a noninvasive biomarker of glymphatic function. Methods Data were drawn from the Alzheimers Disease Neuroimaging Initiative (ADNI) database and a separate validation cohort to analyze the ALPS index in cognitively normal older adults. The relationships among the ALPS index, brain morphometry, and memory performance were examined. Results As a biomarker of glymphatic function, the ALPS index appeared to decline with age in both cohorts. According to the brain morphology analysis, the ALPS index was positively correlated with the thickness of the left entorhinal cortex ( r = 0.258, P false discovery rate (FDR) = 2.96 × 10 -4 ), and it played a mediating role between aging and left entorhinal cortex thinning. The independent cohort further validated the correlation between the ALPS index and the left entorhinal cortex thickness ( r = 0.414, P FDR = 0.042). Additionally, in both the primary and validation cohorts, the ALPS index played a significant mediating role in the relationship between age and durable or delayed memory decline. Conclusion This study highlights the ALPS index as a promising biomarker for glymphatic function and links it to atrophy of the core memory brain regions during aging. Furthermore, these results suggest that targeting glymphatic dysfunction could represent a novel therapeutic approach to mitigate age-related memory decline.