Causal Effect of Lp(a) [Lipoprotein(a)] Level on Ischemic Stroke and Alzheimer Disease

Abstract

Background and Purpose— Stroke and Alzheimer disease are 2 major causes of neurological disability in aged people and shared overlapping predictors. In recent prospective studies, high Lp(a) [lipoprotein(a)] level is associated with high risk of stroke but low risk of Alzheimer disease. Whether this reflects a causal association remains to be established. The aim of 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 Association Study of Stroke consortium with European individuals ≤446 696 individuals. Summary-level data on Alzheimer disease were obtained from the International Genomics of Alzheimer Project With European individuals ≤54 162 individuals. Two-sample Mendelian randomization (MR) estimates were calculated with inverse-variance weighted, penalized inverse-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 substantial increase 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 vessel stroke (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 or cardioembolic stroke. MR-Egger indicated no evidence of pleiotropic bias. Results were broadly consistent in sensitivity analyses using penalized inverse-variance weighted, simple median, weighted median, and MR Pleiotropy Residual Sum and 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 increased risk of large artery stroke but a decreased risk of small vessel stroke and Alzheimer disease. The mechanism underlying the double-edged sword effect of Lp(a) concentrations on neurological system requires further investigation.