Abstract
(AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD
pathology are still not well understood and contradictory results have been reported. We have used a Mendelian
randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD
(LOAD) and test the hypothesis that genetically raised lipid levels increase the risk of LOAD.
Methods and Findings: We included 3,914 patients with LOAD, 1,675 older individuals without LOAD, and 4,989 individuals
from the general population from six genome wide studies drawn from a white population (total n = 10,578). We constructed
weighted genotype risk scores (GRSs) for four blood lipid phenotypes (high-density lipoprotein cholesterol [HDL-c], low-density
lipoprotein cholesterol [LDL-c], triglycerides, and total cholesterol) using well-established SNPs in 157 loci for blood lipids
reported by Willer and colleagues (2013). Both full GRSs using all SNPs associated with each trait at p,561028 and trait specific
scores using SNPs associated exclusively with each trait at p,561028 were developed. We used logistic regression to investigate
whether the GRSs were associated with LOAD in each study and results were combined together by meta-analysis. We found no
association between any of the full GRSs and LOAD (meta-analysis results: odds ratio [OR] = 1.005, 95% CI 0.82–1.24, p = 0.962 per
1 unit increase in HDL-c; OR = 0.901, 95% CI 0.65–1.25, p = 0.530 per 1 unit increase in LDL-c; OR = 1.104, 95% CI 0.89–1.37,
p = 0.362 per 1 unit increase in triglycerides; and OR = 0.954, 95% CI 0.76–1.21, p = 0.688 per 1 unit increase in total cholesterol).
Results for the trait specific scores were similar; however, the trait specific scores explained much smaller phenotypic variance.
Conclusions: Genetic predisposition to increased blood cholesterol and triglyceride lipid levels is not associated with
elevated LOAD risk. The observed epidemiological associations between abnormal lipid levels and LOAD risk could
therefore be attributed to the result of biological pleiotropy or could be secondary to LOAD. Limitations of this study
include the small proportion of lipid variance explained by the GRS, biases in case-control ascertainment, and the limitations
implicit to Mendelian randomization studies. Future studies should focus on larger LOAD datasets with longitudinal
sampled peripheral lipid measures and other markers of lipid metabolism, which have been shown to be altered in LOAD.
Original language | English |
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Journal | PLoS Medicine |
Volume | 11 |
Issue number | 9 |
DOIs | |
Publication status | Published - 16 Sept 2014 |