UC San Diego

Background: As a consequence of an aging world population, cognitive impairment and dementia are growing public health concerns. Previous studies suggest that kidney dysfunction is associated with cognitive decline. Most studies were limited to one marker of kidney function, and the extent to which associations are modified by genetics has received little consideration. Moreover, whether these associations are causal is not clear.

Methods: This dissertation is composed of three studies. Study one was a longitudinal study conducted among 1,634 participants from the Rancho Bernardo Study of Healthy Aging (RBS), who had repeated measures of kidney function and cognitive follow-up of up to 24 years. Study two was a cross-sectional study using data from up to 341,208 participants from the UK Biobank (UKBB) with three different measures of kidney function, genetic data, and cognitive function data from the baseline assessment. Study three used data from 357,590 UKBB participants to assess causal associations between biomarkers of kidney function and cognitive performance using a Mendelian Randomization (MR) approach.

Results: In study one, men with albuminuria (urine albumin-to-creatinine ratio [ACR] ≥25 mg/g for men and ACR ≥30 mg/g for women) had faster cognitive decline across multiple domains. High serum uric acid (SUA) was related to lower baseline global cognitive function scores in men. There was no association between kidney function and cognitive performance in women. In study two, albuminuria, creatinine-based estimated glomerular filtration rate (GFRcre) <60ml/min, and cystatin C-based estimated glomerular filtration rate (eGFRcys) <60ml/min were associated with worse cognitive performance, and associations were more robust with eGFRcys versus eGFRcre. The association between albuminuria and reaction time was modified by a polygenic score for cognitive function. In the third study, genetically increased ACR was associated with reaction time, but there was no evidence to support causal effects of SUA, eGFRcre or eGFRcys on cognitive ability.

Conclusions: Multiple markers of kidney function were associated with worse cognitive performance in individuals of European descent. Furthermore, these associations may be modified by sex and genetics. Albuminuria may directly influence cognition, however SUA, eGFRcre and eGFRcys levels do not appear to be causally associated with cognitive performance.