Relationship of urate-lowering drugs with cognition and dementia: A Mendelian randomization and observational study

Prior studies have presented paradoxical results regarding the association of uric acid-lowering drugs (ULDs) therapy with cognition and dementia. We aimed to explore this correlation. In this observational study, we extracted and analyzed the data from the National Health and Nutrition Examination Survey (NHANES) database and the FDA Adverse Event Reporting System (FAERS) database to investigate the association of ULDs with cognitive function and dementia. Two-simple Mendelian randomization (MR) and multivariable MR (MVMR) analyses were conducted to evaluate the causal associations of ULDs for all common types of dementia, including Alzheimer's disease (AD), vascular dementia (VD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). In the NHANES database, regardless of whether ULDs were included only or adjusted for covariates, the linear regression models did not find a correlation between ULDs and three cognitive tests (all p > 0.05). In the FAERS database, the dementia signal in ULDs lost significance after stepwise constraints (the lower limit of proportional reporting ratio lower than 1). In the two-sample MR analysis, allopurinol was associated with an increased risk of VD (OR = 123.747, p = 0.002), and a positive causal relationship was found between uricosuric drugs and AD (OR = 1.003, p = 0.003). However, the significance disappeared after adjusting for risk factors of dementia (p > 0.05). This study indicates that ULDs may not be related to an increase or decrease risk of cognition function and dementia, including all common types of dementia (AD, VD, FTD, and DLB).