Abstract
BACKGROUND: Cognitive decline in postmenopausal women is a growing public health concern, with estrogen deficiency linked to brain aging. However, the role of the brain's lymphatic-like system-assessed via the diffusion tensor imaging along the perivascular space (DTI-ALPS) index-in mediating estrogen-cognitive associations remains unclear. This study investigated whether the DTI-ALPS index mediates the relationship between estrogen levels and cognitive function in postmenopausal women. METHODS: Data from 55 women recruited from outpatient clinics were analyzed. A combination of traditional and advanced statistical methods was used. These included MANOVA, non-linear correlation analysis, structural equation modeling, and machine learning algorithms. RESULTS: Postmenopausal women exhibited lower right and mean ALPS indices (P < 0.05) and worse cognitive performance on reaction time tasks (P < 0.05). The mean ALPS index fully mediated the relationship between estrogen and cognitive accuracy (e.g., Stroop: r = 0.588, P < 0.01), with machine learning ranking ALPS index and estrogen as top predictors of cognitive function. CONCLUSIONS: Reduced brain lymphatic function (lower ALPS index) is associated with cognitive decline in postmenopausal women, and this relationship is mediated by estrogen levels. The DTI-ALPS index may serve as a novel biomarker for menopause-related cognitive health.