Low LDL cholesterol, <i>PCSK9</i> and <i>HMGCR</i> genetic variation, and risk of Alzheimer's disease and Parkinson's disease: Mendelian randomisation study.

Abstract

<b>Objective</b> To test the hypothesis that low density lipoprotein (LDL) cholesterol due to genetic variation in the genes responsible for LDL cholesterol metabolism and biosynthesis(<i>PCSK9</i> and 3-hydroxy-3-methylglutaryl-CoA reductase (<i>HMGCR</i>), respectively) is associated with a high risk of Alzheimer's disease, vascular dementia, any dementia, and Parkinson's disease in the general population.<b>Design</b> Mendelian randomisation study.<b>Setting</b> Copenhagen General Population Study and Copenhagen City Heart Study.<b>Participants</b> 111 194 individuals from the Danish general population.<b>Main outcome measures</b> Risk of Alzheimer's disease, vascular dementia, all dementia, and Parkinson's disease.<b>Results</b> In observational analyses, the multifactorially adjusted hazard ratio for Parkinson's disease in participants with an LDL cholesterol level <1.8 mmol/L versus ≥4.0 mmol/L was 1.70 (95% confidence interval 1.03 to 2.79), whereas the corresponding hazard ratios for Alzheimer's disease, vascular dementia, or any dementia did not differ from 1.0. <i>PCSK9</i> and <i>HMGCR</i> variants combined were associated with a 9.3% lower LDL cholesterol level. In genetic, causal analyses adjusted for age, sex, and year of birth, the risk ratios for a lifelong 1 mmol/L lower LDL cholesterol level were 0.57 (0.27 to 1.17) for Alzheimer's disease, 0.81 (0.34 to 1.89) for vascular dementia, 0.66 (0.34 to 1.26) for any dementia, and 1.02 (0.26 to 4.00) for Parkinson's disease. Summary level data from the International Genomics of Alzheimer's Project using Egger Mendelian randomisation analysis gave a risk ratio for Alzheimer's disease of 0.24 (0.02 to 2.79) for 26 <i>PCSK9</i> and <i>HMGCR</i> variants, and of 0.64 (0.52 to 0.79) for 380 variants of LDL cholesterol level lowering.<b>Conclusion</b> Low LDL cholesterol levels due to <i>PCSK9</i> and <i>HMGCR</i> variants had no causal effect on high risk of Alzheimer's disease, vascular dementia, any dementia, or Parkinson's disease; however, low LDL cholesterol levels may have a causal effect in reducing the risk of Alzheimer's disease.