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Alzheimer Disease / Disease Models, Animal / Alzheimer's Disease · Journal article
Experimental Neurology · August 26, 2026
Early or partial results. Treat as a signal, not a conclusion.
This is a translational hypothesis-generating study integrating murine models, cross-sectional human NHANES data, and in vitro mechanistic exploration, reporting a significant inverse non-linear association between blood urea nitrogen and low cognitive performance in older adults that plateaus above approximately 12 mg/dL. The authors explicitly frame findings as exploratory and call for independent prospective validation, and the mechanistic pathway via GLS-mediated mitochondrial oxidative phosphorylation remains speculative.
Integrated translational study: murine models (transgenic vs. wild-type), cross-sectional observational analysis of NHANES data, in silico gene knockout in cultured human kidney cells. Murine: 5xFAD transgenic mice and wild-type controls; Human: NHANES participants (older adult cohort, specific eligibility criteria not detailed); Cellular: cultured human kidney cells. Intervention: Measurement of blood urea nitrogen (BUN) and cognitive performance; virtual GLS gene knockout in kidney cells. Compared with: Wild-type mice vs. 5xFAD; high BUN vs. low BUN in humans; GLS-intact vs. GLS-knockout kidney cells. n = 3,435. Not specified; NHANES is US-based national survey.
5xFAD mice exhibited early renal histopathological damage and memory deficits; BUN positively correlated with fear memory retention in murine models In humans (n=3435), restricted cubic splines revealed significant inverse association between BUN and low cognitive performance, with risk reduction plateauing at BUN levels above approximately 12 mg/dL Subgroup analyses showed no significant interactions across population strata, indicating consistent inverse association across examined variables
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BUN may warrant evaluation as an accessible peripheral biomarker for cognitive risk assessment in older populations. However, the cross-sectional design prevents causal attribution, and mechanistic understanding via GLS is purely exploratory; independent prospective validation in external cohorts is essential before clinical consideration.
Cross-species translational study with human observational data showing a novel non-linear association, but limited by lack of prospective design, mechanistic uncertainty, and authors' own call for validation in independent cohorts.
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BUN may warrant evaluation as an accessible peripheral biomarker for cognitive risk assessment in older populations. However, the cross-sectional design prevents causal attribution, and mechanistic understanding via GLS is purely exploratory; independent prospective validation in external cohorts is essential before clinical consideration.
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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.
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