Albuminuria and Estimated GFR as Risk Factors for Dementia in Midlife and Older Age: Findings From the ARIC Study

Rationale & Objective: Evidence is limited on how estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR) relate to dementia at different ages. We evaluated eGFR and UACR in midlife and older age as risk factors for dementia. Additionally, we assessed whether the association between eGFR and dementia is altered when cystatin C and β₂-microglobulin (B2M) levels are used for GFR estimation. Study Design: Prospective cohort study. Setting & Participants: Two baselines from the Atherosclerosis Risk in Communities (ARIC) Study were used: visit 4 (1996-1998), including 9,967 participants 54 to 74 years old, and visit 5 (2011-2013), including 4,626 participants 70 to 90 years old. Participants were followed up until 2017. Predictors: Log(UACR); eGFR based on creatinine, cystatin C, creatinine and cystatin C, or B2M levels (denoted as eGFR_cr, eGFR_cys, eGFR_cr-cys, and eGFR_B2M). Outcome: Incident dementia. Analytical Approach: Multivariable Cox proportional hazards regression models fit separately for each of the 5 predictors and based on a change in the predictor equivalent to the interquartile range for that predictor at visit 4 (IQR_V4). eGFR models were adjusted for log(UACR) and log(UACR) models were adjusted for eGFR_cys. Results: We observed 1,821 dementia cases after visit 4 and 438 cases after visit 5. Dementia risk increased with higher albuminuria levels (HRs per IQR_V4 [equivalent to 4.2-fold greater log albuminuria] of 1.15 [95% CI, 1.09-1.21] after visit 4 and 1.27 [95% CI, 1.13-1.42] after visit 5). An association with lower eGFR was seen for only eGFR_cys (HRs per IQR_V4 [equivalent to 24.3 mL/min/1.73 m² lesser eGFR_cys] of 1.12 [95% CI, 1.04-1.21] after visit 4 and 1.30 [95% CI, 1.12-1.52] after visit 5) and eGFR_B2M (HRs per IQR_V4 [equivalent to 18.3 mL/min/1.73 m² lesser eGFR_B2M] of 1.15 [95% CI, 1.07-1.23] after visit 4 and 1.34 [95% CI, 1.17-1.55] after visit 5). Differences between these associations in midlife and older age were not statistically significant. Limitations: Changes in potentially time-varying covariates were not measured. Dementia was not subclassified by cause. Conclusions: Albuminuria was consistently associated with dementia incidence. Lower eGFR based on cystatin C or B2M, but not creatinine, levels was also associated with dementia. Risk associations were similar when kidney measures were assessed at midlife and older age.