Lipoprotein(a) (Lp[a]) is a circulating lipoprotein with proatherogenic, proinflammatory, and possibly prothrombotic properties. Circulating Lp(a) levels are largely genetically determined, in particular, by the LPA gene. As such, genetic variants at the LPA locus can serve as instrumental variables for investigating the clinical effects of circulating Lp(a) levels. Mendelian randomization (MR) studies have shown that elevated Lp(a) levels are associated with a higher risk of coronary artery disease1–3 and aortic valve stenosis.2–4 Evidence on the causal role of elevated Lp(a) levels for other atherosclerotic and specific valvular diseases is limited, although there are MR data supporting a positive association between genetically predicted Lp(a) levels and peripheral artery disease.2,3 Whether Lp(a) is causally related to thrombotic disease and cerebrovascular disease remains unclear.2,3,5

In this study, we used the UK Biobank cohort to perform an MR investigation into the causal effects of circulating Lp(a) levels on atherosclerotic, cerebrovascular, thrombotic, and valvular diseases. Because a recent MR study provided evidence of an inverse association of Lp(a) levels with Alzheimer disease,5 we additionally explored whether genetically predicted Lp(a) levels are associated with Alzheimer disease and dementia.