{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T04:53:27Z","timestamp":1785041607543,"version":"3.55.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>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\u2014the combined effect of LDL-C magnitude and duration over time\u2014captures 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.<\/jats:p>","DOI":"10.3389\/fneur.2026.1836134","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T04:43:57Z","timestamp":1777351437000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Long-term LDL cholesterol burden and stroke: mechanistic insights and emerging strategies for personalized lipid management"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhuanfang","family":"Li","sequence":"first","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinping","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Operation Center, Huashan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1177\/17474930241308142","article-title":"World stroke organization: global stroke fact sheet 2025","volume":"20","author":"Feigin","year":"2025","journal-title":"Int J Stroke"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1547714","DOI":"10.3389\/fneur.2025.1547714","article-title":"Systematic analysis of the burden of ischemic stroke attributable to high LDL-C from 1990 to 2021","volume":"16","author":"Tang","year":"2025","journal-title":"Front Neurol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2313","DOI":"10.1093\/eurheartj\/ehz962","article-title":"Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the european atherosclerosis society consensus panel","volume":"41","author":"Bor\u00e9n","year":"2020","journal-title":"Eur Heart J"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s13167-024-00356-6","article-title":"The paradigm change from reactive medical services to 3PM in ischemic stroke: a holistic approach utilising tear fluid multi-omics, mitochondria as a vital biosensor and AI-based multi-professional data interpretation","volume":"15","author":"Golubnitschaja","year":"2024","journal-title":"EPMA J"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1038\/s41569-024-01039-5","article-title":"The LDL cumulative exposure hypothesis: evidence and practical applications","volume":"21","author":"Ference","year":"2024","journal-title":"Nat Rev Cardiol"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.1001\/jamacardio.2021.3508","article-title":"Association between cumulative low-density lipoprotein cholesterol exposure during young adulthood and middle age and risk of cardiovascular events","volume":"6","author":"Zhang","year":"2021","journal-title":"JAMA Cardiol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"2459","DOI":"10.1093\/eurheartj\/ehx144","article-title":"Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. 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