The Effects of Statins on Cognitive Performance Are Mediated by Low-Density Lipoprotein, C-Reactive Protein, and Blood Glucose Concentrations

Abstract

Statins are widely used for cardiovascular disease prevention but their effects on cognition remain unclear. Statins reduce cholesterol concentration and have been suggested to provide both beneficial and detrimental effects. Our aim was to investigate the cross-sectional and longitudinal association between statin use and cognitive performance, and whether blood low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, glucose, C-Reactive Protein (CRP), and vitamin D biomarkers mediated this association. We used participants from the UK biobank aged 40 to 69 without neurological and psychiatric disorders (n = 147,502 and n = 24,355, respectively). We performed linear regression to evaluate the association between statin use and cognitive performance and, mediation analysis to quantify the total, direct, indirect effects and the proportion meditated by blood biomarkers. Statin use was associated with lower cognitive performance at baseline (β = -0.40 [-0.53, -0.28], P = <.0001) and this association was mediated by LDL (Proportion mediated = 51.4%, P = 0.002), CRP (Proportion mediated = -11%, P = 0.006) and blood glucose (Proportion mediated = 2.6%, P = 0.018) concentrations. However, statin use was not associated with cognitive performance, measured 8 years later (β = -0.003 [-0.11, 0.10], P = 0.96). Our findings suggest that statins are associated with lower short-term cognitive performance by lowering LDL and raising blood glucose concentrations, and better performance by lowering CRP concentrations. In contrast, statins have no effect on long-term cognition and remain beneficial in reducing cardiovascular risk factors.

Consideration of T-Cell Profile in the Examination of Statin Efficacy in Inflammatory Diseases, Neurodegeneration, and Neurocognitive Performance

“…Based on this model, one would hypothesize that statin usage may improve long-term cognitive performance in AD patient subpopulations that have higher baseline inflammatory status but might have short-term negative effects on cognitive performance in patients with more normal T-cell profiles. Indeed, a recent study by Gentreau and colleagues investigated the relationship between statin use and cognitive performance at both acute and chronic time points, finding that statin use was negatively associated with cognitive performance at short time points but not after 8 years of treatment ( 23 ). Interestingly, reductions in LDL cholesterol from statin therapy were highly negatively associated with cognitive performance, whereas reductions in CRP, an inflammatory marker, were positively associated with cognitive outcomes.…”