Causal effect of Lp(a) [lipoprotein(a)] level on ischemic stroke and alzheimer disease a mendelian randomization study

Abstract

Background and Purpose-Stroke and Alzheimer disease are 2 major causes of neurological disability in aged people andshared overlapping predictors. In recent prospective studies, high Lp(a) [lipoprotein(a)] level is associated with high riskof stroke but low risk of Alzheimer disease. Whether this reflects a causal association remains to be established. The aimof this study is to examine the causal associations of Lp(a) concentrations on ischemic stroke, ischemic stroke subtypes,and Alzheimer disease.Methods-We used 9 single-nucleotide polymorphisms associated with Lp(a) concentrations as instrumental variables.Summary-level data on ischemic stroke and its subtypes were obtained from the Multiancestry Genome-Wide AssociationStudy of Stroke consortium with European individuals =446696 individuals. Summary-level data on Alzheimer diseasewere obtained from the International Genomics of Alzheimer Project With European individuals =54162 individuals.Two-sample Mendelian randomization (MR) estimates were calculated with inverse-variance weighted, penalizedinverse-variance weighted, simple median, weighted median, and MR Pleiotropy Residual Sum and Outlier approaches,and MR-Egger regression was used to explore pleiotropy.Results-Genetically predicted 1-SD log-transformed increase in Lp(a) concentrations was associated with a substantialincrease in risk of large artery stroke (odds ratio, 1.20; 95% CI, 1.11-1.30; P<0.001) and a reduce in risk of small vesselstroke (odds ratio, 0.92; 95% CI, 0.88-0.97; P=0.001) and Alzheimer disease (odds ratio, 0.94; 95% CI, 0.91-0.97;P<0.001) using inverse-variance weighted method. No significant association was observed for total ischemic stroke orcardioembolic stroke. MR-Egger indicated no evidence of pleiotropic bias. Results were broadly consistent in sensitivityanalyses using penalized inverse-variance weighted, simple median, weighted median, and MR Pleiotropy Residual Sumand Outlier approaches accounting for potential genetic pleiotropy or outliers.Conclusions-This study provides evidence to support that high Lp(a) concentrations was causally associated with an increasedrisk of large artery stroke but a decreased risk of small vessel stroke and Alzheimer disease. The mechanism underlyingthe double-edged sword effect of Lp(a) concentrations on neurological system requires further investigation.