Abstract
BACKGROUND: Dementia is a leading cause of cognitive decline, with Alzheimer's disease (AD) and vascular dementia (VaD) being the most common subtypes. The intraindividual difference between the estimated glomerular filtration rate based on cystatin C and creatinine (eGFRdiff) may serve as an indicator of the overall health status of an individual. However, the relationships between the eGFRdiff and dementia risk, dementia subtypes, dementia-related neuroimaging changes, and cognitive functions remain unclear. METHODS: This study analysed data from over 450,000 participants in the UK Biobank who were followed for up to 15 years. The estimated glomerular filtration rate based on cystatin C (eGFRcys) and creatinine (eGFRcr) was calculated using the CKD-EPI equation, and eGFRdiff was defined as the difference between these values (eGFRdiff = eGFRcys - eGFRcr). Multivariate Cox regression models were used to evaluate the associations between the eGFRdiff and all-cause dementia (ACD), AD, and VaD, whereas cross-sectional analysis were used to examine the relationship among the eGFRdiff, dementia-related neuroimaging changes, and cognitive functions. RESULTS: Over a median follow-up of 13.5 years, 8,710 participants developed dementia, including 3,910 with AD and 1,893 with VaD. Each one standard deviation increase in eGFRdiff was associated with a reduced risk of dementia, with hazard ratios (95% confidence intervals) of 0.92 (0.90-0.94) for ACD, 0.94 (0.91-0.98) for AD, and 0.90 (0.85-0.94) for VaD. A negative eGFRdiff was associated with adverse neuroimaging changes, including lower total brain and gray matter volumes and higher white matter hyperintensities. Additionally, a negative eGFRdiff was associated with poorer performance across multiple cognitive domains. CONCLUSION: A negative eGFRdiff was associated with an increased risk of dementia, adverse neuroimaging outcomes, and cognitive decline. These findings suggest that the eGFRdiff might be considered a potential associative indicator for dementia and cognitive impairment, suggesting potential clinical value in risk assessment and early intervention strategies.