Cognitive reserve, plasma proteomics, and adverse kidney outcomes

Background: Cognitive Reserve (CR) may protect against age-related diseases, but its relationship with kidney outcomes and underlying proteomic mechanisms is unclear. We examined associations of CR with incident Chronic Kidney Disease (CKD), End-Stage Renal Disease (ESRD), and all-cause mortality, and explored plasma protein mediators.

Methods: We conducted analyses in three subsamples of UK Biobank participants: 
(1) 108,963 individuals without baseline CKD for incident CKD; 
(2) 20,010 with prevalent CKD for ESRD and all cause mortality; and 
(3) 9,842 participants (a subset of the first subsample) with available plasma proteomic data. Latent class analysis derived low, moderate, and high CR based on education, occupation, confiding, social contact, leisure, and TV time. CR associated proteins were identified by LASSO regression. Mediation analysis quantified the proportion of the CR–CKD association explained by these proteins. Mendelian Randomization (MR) using protein quantitative trait loci provided causal evidence.

Results: Over a median follow up of 13.6 years, we documented 5,688 incident CKD (subsample 1), 469 ESRD, and 3,679 deaths (subsample 2). High versus low CR was associated with lower risks of incident CKD (HR=0.68, 95%CI:0.63–0.73), ESRD (HR=0.75, 95% CI: 0.59–0.96), and all-cause mortality (HR=0.70, 95% CI: 0.63–0.76). In the proteomics subsample (subsample 3), we identified 155 CR-related proteins, enriched in immune regulation and chemokine pathways; 55 significantly mediated the CR–CKD association, with a total mediation proportion of 46.1% (95% CI: 27.6%–61.7%). MR supported a potential causal link between CHI3L1 and CKD.

Conclusions: Higher CR is associated with lower risks of CKD, ESRD, and mortality. The protective effect on CKD is partially mediated by plasma proteins involved in immune and chemokine signaling. Enhancing CR through life-course interventions may offer a novel strategy for preventing adverse kidney outcomes, and the identified protein signature offers new insights into the brain–kidney axis.

Keywords: Cognitive reserve; Chronic kidney disease; End-stage renal disease; Proteomics; UK Biobank.

Rui Zhou is an associate research fellow and Master’s supervisor in Epidemiology and Biostatistics at Guangdong Pharmaceutical University, and a “Pazhou Scholar” at Guangdong Second Provincial General Hospital. Her research focuses on epidemiological studies of cardiometabolic risk factors and aging-related diseases. She serves as a reviewer for multiple international journals and on the Youth Editorial Board of Guangdong Medical Journal. She has led several funded projects, including the National Natural Science Foundation of China, and has published 20 SCI papers as first/corresponding author in journals such as J Hepatol (IF=40.1), with over 1,340 citations and an H-index of 21.