Long-term LDL cholesterol burden and stroke: mechanistic insights and emerging strategies for personalized lipid management

Low-density lipoprotein cholesterol (LDL-C) is a causal and modifiable driver of atherosclerotic cardiovascular disease and an important contributor to atherosclerotic ischemic stroke. Increasing evidence suggests that cumulative LDL-C exposure-the combined effect of LDL-C magnitude and duration over time-captures vascular injury more accurately than a single measurement obtained at one clinical encounter. This review uses cumulative LDL-C exposure as an organizing framework for stroke prevention. We summarize current approaches to quantifying long-term LDL-C burden, review epidemiological evidence linking cumulative exposure to incident and recurrent ischemic stroke, and discuss biological mechanisms that may explain these associations. We then examine how lipid-lowering therapies, including statins, PCSK9 inhibitors, and small-interfering RNA-based agents, may reduce cumulative vascular injury. Particular attention is paid to the clinical challenge of balancing ischemic benefit against potential hemorrhagic vulnerability in selected high-risk phenotypes, such as patients with probable cerebral amyloid angiopathy or multiple lobar cerebral microbleeds. We propose a precision-management framework that integrates longitudinal lipid exposure, stroke subtype, genetics, neuroimaging, and dynamic risk assessment. By shifting attention from static lipid values to lifelong exposure, cumulative LDL-C burden may offer a more coherent basis for individualized cerebrovascular prevention.