Abstract 19109: Low PCSK9 and LDL Cholesterol and Risk of Dementia, Parkinson’s Disease, and Epilepsy - A Mendelian Randomization Study
Introduction: Low levels of low-density-lipoprotein cholesterol(LDL-C) due to statin use has been associated with reduced cognitive function. We aimed to assess whether low LDL-C due to genetic variation in the 3-hydroxy-3-methylglutaryl-CoA reductase(HMGCR; rs17238484) and proprotein convertase subtilisin kexin 9(PCSK9; rs11591147, rs148195424, rs562556, rs505151) genes, involved in LDL-C biosynthesis and metabolism, respectively, is associated with risk of Alzheimer’s dementia, vascular dementia, all dementia, Parkinson’s disease, and epilepsy in a general population off and on lipid lowering medication.
Methods: We examined associations of plasma LDL-C with observational risk of disease; genetic variants with plasma LDL-C levels; and genetic variants and risk of disease as an indication of causality using a Mendelian randomization design in 92,068 participants off and 11,519 participants on lipid lowering medication from the Copenhagen General Population Study and the Copenhagen City Heart Study.
Results: In observational analysis, risk of epilepsy was 98%(95% confidence interval: 32%-297%) higher in participants with an LDL-C <1.5mmol/L versus ≥3.0mmol/L. Low LDL-C was not associated with risk of Alzheimer’s dementia, vascular dementia, all dementia, and Parkinson’s disease. In causal genetic analyses, PCSK9 and HMGCR variants associated with 7.8% and 2.9% lower LDL-C. Genotypes were not associated with risk of Alzheimer’s dementia, vascular dementia, all dementia, Parkinson’s disease, or epilepsy.
Conclusions: Using 103,587 individuals from the general population, we found that observationally low LDL-C level was associated with increased risk of epilepsy. Low LDL-C due to PCSK9 and HMGCR variants was not associated with Alzheimer’s dementia, vascular dementia, all dementia, Parkinson’s disease or epilepsy, and results does not support a causal role of low LDL-C in these diseases.
- Low density lipoprotein cholesterol
- Parkinson’s disease
- Alzheimer’s disease
- Lipid lowering treatment
Author Disclosures: M. Benn: None. B.G. Nordestgaard: None. R. Frikke-Schmidt: None. A. Tybjærg-Hansen: None.
- © 2015 by American Heart Association, Inc.