The presence of aggregation-prone LDL in plasma is associated with the risk of cardiovascular-related death in patients with coronary artery disease (CAD), independently of conventional risk factors. According to a study in which researchers used a novel method to assess the susceptibility of LDL to aggregate during ex vivo lipolysis induced by human recombinant secretory sphingomyelinase, differences in the LDL lipidome determine the susceptibility of LDL to aggregate, with aggregation-prone LDL containing more sphingolipids and fewer phosphatidylcholines than aggregation-resistant LDL. Pharmacological and genetic interventions to alter the LDL composition and lower its aggregation susceptibility led to slowed development of atherosclerosis in animal models. In humans, PCSK9 inhibition or a healthy diet induced similar changes in LDL composition that reduced its aggregation susceptibility. This study suggests that the propensity of LDL to aggregate can serve as a biomarker and that LDL aggregation can be modified by nutritional and medical interventions.