Non-linear association of blood urea nitrogen with low cognitive performance: Translational evidence from murine models and human population analysis.

Background

Cognitive impairment in Alzheimer's disease (AD) is increasingly recognized as a systemic metabolic disorder, yet early peripheral biomarkers remain elusive. The kidney-brain axis offers a novel perspective, but the association between blood urea nitrogen (BUN) and Cognitive function is poorly understood.

Methods

We integrated murine models (5xFAD vs. wild-type), human NHANES data (n = 3435), and single-cell virtual knockout of the BUN-associated gene GLS in human kidney cells.

Results

5xFAD mice showed early renal histopathological damage and memory deficits; BUN positively correlated with fear memory retention, and reduced BUN in 5xFAD aligned with the low-BUN risk limb of the human non-linear association. In humans, restricted cubic splines revealed a significant inverse association between BUN and low cognitive performance (LCP), with the risk reduction plateauing at BUN levels above approximately 12 mg/dL. Subgroup analyses showed no significant interactions for any of the examined variables, indicating that the inverse association between BUN and LCP was consistent across population strata. Exploratory GLS knockout upregulated mitochondrial oxidative phosphorylation and ROS pathways, providing hypothesis-generating molecular clues.

Conclusions

Cross-species evidence links BUN to cognitive, with murine data consistent with human low-BUN risk and identifying a significant inverse association between BUN and LCP that plateaued above approximately 12 mg/dL in this older adult cohort in this cohort, which should be viewed as exploratory and requires validation in independent prospective cohorts. Virtual GLS knockout suggests a mitochondrial axis. BUN warrants further evaluation as an accessible biomarker for cognitive risk assessment.