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Genetic Predisposition to Low-Density Lipoprotein Cholesterol May Increase Risks of Both Individual and Familial Alzheimer's Disease.

ABSTRACT: Background: Previous observational studies provided conflicting results on the association between low-density lipoprotein cholesterol (LDL-C) level and the risk of Alzheimer's disease (AD). Objective: We used two-sample Mendelian randomization (MR) study to explore the causal associations between LDL-C level and the risks of individual, paternal, maternal, and family history of AD. Methods: Summary-level genetic data for LDL-C were acquired from results of the UK Biobank GWAS. Corresponding data for paternal, maternal, and family history of AD were obtained from the NHGRI-EBI Catalog of human genome-wide association studies. Data for individual AD were obtained from the MR-Base platform. A two-sample MR study was performed to explore the causal association between LDL-C level and the risks of individual, paternal, maternal, and family history of AD. Results: Genetically predicted LDL-C was positively associated with individual [Odds ratio (OR) = 1.509, 95% confidence interval (CI) = 1.140-1.999; P = 4.0 × 10^-3], paternal [OR = 1.109, 95% CI = 1.053-1.168; P = 9.5 × 10^-5], maternal [OR = 1.132, 95% CI = 1.070-1.199; P = 2.0 × 10^-5], and family history of AD [OR = 1.124, 95% CI = 1.070-1.181; P = 3.7 × 10^-6] in inverse variance weighted analysis. After performing weighted median and MR-Egger analysis, consistent results were observed. There was no horizontal pleiotropy in the two-sample MR analysis. Conclusions: High level of LDL-C may increase the risks of both individual and familial AD. Decreasing the LDL-C to a reasonable level may help to reduce the related risk.

SUBMITTER: Tan JS

PROVIDER: S-EPMC8787049 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background MEDI6012 is recombinant human lecithin cholesterol acyltransferase, the rate-limiting enzyme in reverse cholesterol transport. Infusions of lecithin cholesterol acyltransferase have the potential to enhance reverse cholesterol transport and benefit patients with coronary heart disease. The purpose of this study was to test the safety, pharmacokinetic, and pharmacodynamic profile of MEDI6012. Methods and Results This phase 2a double-blind study randomized 48 subjects with stable coronary heart disease on a statin to a single dose of MEDI6012 or placebo (6:2) (NCT02601560) with ascending doses administered intravenously (24, 80, 240, and 800 mg) and subcutaneously (80 and 600 mg). MEDI6012 demonstrated rates of treatment-emergent adverse events that were similar to those of placebo. Dose-dependent increases in high-density lipoprotein cholesterol were observed with area under the concentration-time curves from 0 to 96 hours of 728, 1640, 3035, and 5318 should be: mg·h/mL in the intravenous dose groups and 422 and 2845 mg·h/mL in the subcutaneous dose groups. Peak mean high-density lipoprotein cholesterol percent change was 31.4%, 71.4%, 125%, and 177.8% in the intravenous dose groups and 18.3% and 111.2% in the subcutaneous dose groups, and was accompanied by increases in endogenous apoA1 (apolipoprotein A1) and non-ATP-binding cassette transporter A1 cholesterol efflux capacity. Decreases in apoB (apolipoprotein B) were observed across all dose levels and decreases in atherogenic small low-density lipoprotein particles by 41%, 88%, and 79% at the 80-, 240-, and 800-mg IV doses, respectively. Conclusions MEDI6012 demonstrated an acceptable safety profile and increased high-density lipoprotein cholesterol, endogenous apoA1, and non-ATP-binding cassette transporter A1 cholesterol efflux capacity while reducing the number of atherogenic low-density lipoprotein particles. These findings are supportive of enhanced reverse cholesterol transport and a functional high-density lipoprotein phenotype. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02601560.

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Genetic Predisposition to Low-Density Lipoprotein Cholesterol May Increase Risks of Both Individual and Familial Alzheimer's Disease.

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