Top Things to Know: Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke
Published: September 14, 2023
- A high plasma level of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerotic cardiovascular disease (ASCVD) with a continuous, direct relationship (dose-response) between plasma LDL-C and ASCVD risk.
- More aggressive LDL-C reduction correlates with lower risk of myocardial infarction, ischemic stroke, need for coronary and peripheral revascularization, death, and rates of progression of ASCVD.
- The brain is the body’s most cholesterol-rich organ and some have questioned whether aggressive LDL-C lowering induces abnormal structural and functional changes. The objective of this scientific statement is to evaluate contemporary evidence which either supports or refutes the conclusion that aggressive LDL-C-lowering or lipid-lowering exerts toxic effects on the brain leading to cognitive impairment/dementia or hemorrhagic stroke.
- The content of cholesterol in the brain is largely isolated from peripheral circulation levels by the blood-brain barrier. Mechanisms exist for the movement of cholesterol into the brain, but is largely independent of levels in the systemic circulation.
- Although there are numerous gaps in understanding the role of cholesterol, its biosynthesis, compartmentalization, and its intracellular and extracellular metabolism in the brain, there is very little mechanistic evidence supporting a possible causal effect of cholesterol lowering medications on the development of neurodegeneration.
- Although some retrospective, case control, and prospective longitudinal studies suggest that statins and LDL-C lowering are associated with cognitive impairment or dementia, the preponderance of observational studies and data from randomized trials do not support this conclusion.
- However, it is clear that lower LDL-C correlates with lower risk of overall stroke and stroke recurrence, mostly related to a reduction in ischemic stroke.
- Randomized placebo-controlled studies of ezetimibe and PCSK9 inhibitor have also failed to find an association between these LDL-lowering therapies and dementia or impaired cognition, regardless of the LDL-C achieved.
- The risk of a hemorrhagic stroke associated with statin therapy in patients without a history of cerebrovascular disease is non-significant and achieving very low levels of LDL-C does not appear to increase that risk.
- Data reflecting the risk of hemorrhagic stroke associated with lipid-lowering treatment among patients with a history of hemorrhagic stroke is not robust and requires additional research.
Citation
Goldstein LB, Toth PP, Dearborn-Tomazos JL, Giugliano RP, Hirsh BJ, Peña JM, Selim MH, Woo D; on behalf of the American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Peripheral Vascular Disease; and Stroke Council. AggressiveLDL-C lowering and the brain: impact on risk for dementia and hemorrhagic stroke: a scientific statementfrom the American Heart Association [published online ahead of print September 14, 2023]. Arterioscler Thromb Vasc Biol. doi: 10.1161/ATV.0000000000000164