Causal relationship between cholesterol-lowering therapy and Alzheimer Disease: evidence from genetic correlation and Mendelian randomization study

Abstract

AbstractThe objective of this study was to investigate the causal relationship between cholesterol-lowering therapy and Alzheimer's disease (AD) using Mendelian Randomization (MR) with two sets of genetic instruments derived from UK Biobank, GLGC, and GWAS ATLAS. Instrumental variables were selected based on SNPs that were significantly associated with lipid-lowering drugs or targets, but not with outcome or confounding factors. The primary analysis was conducted using inverse variance weighted (IVW), MR-PRESSO, WM. Cochran Q, and MR pleiotropy tests to assess heterogeneity or pleiotropy. The results revealed that cholesterol-lowering drugs did not show a significant effect on AD risk with IVW (Atorvastatin: OR = 0.943, 95% CI = 0.612–1.453, p = 0.789; Pravastatin: OR = 6.857, 95% CI = 0.514–90.864, p = 0.144; Rosuvastatin: OR = 2.466, 95% CI = 0.333–18.278, p = 0.377; Simvastatin: OR = 1.138, 95% CI = 0.976–1.328, p = 0.098; Ezetimibe: OR = 1.292, 95% CI = 0.239-6,969, p = 0.766). Further multivariable and target MR analyses (HMGCR, NPC1L1, and PSCK9) also demonstrated that the combination of statins and ezetimibe, or their pharmacological targets, did not show a significant causal relationship with AD. Therefore, based on the current evidence, it can be concluded that there is no causal relationship between cholesterol-lowering drugs and AD.