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.
Highlights
Alzheimer’s disease (AD), the most prevalent type of neurodegenerative disorder, is characterized by a progressive and irreversible decline in memory, thinking, and cognitive skills
Predicted low-density lipoprotein cholesterol (LDL-C) was significantly positively associated with individual AD [Odds ratio (OR) = 1.509, 95% confidence interval (CI) = 1.140–1.999; P = 4.0 × 10−3], paternal history of AD [OR = 1.109, 95% CI = 1.053– 1.168; P = 9.5 × 10−5], maternal history of AD [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] (Figure 2)
By performing the two-sample Mendelian randomization (MR) analysis, we identified the causal association between higher LDL-C level and increased AD risk
Summary
Alzheimer’s disease (AD), the most prevalent type of neurodegenerative disorder, is characterized by a progressive and irreversible decline in memory, thinking, and cognitive skills. As lipid fractions represent modifiable potential targets for prevention, exploring their relationship with AD risk is of great significance. Some studies reported that patients with AD exhibited a higher level of LDL-C than normal controls [7, 8]. Other studies reported no significant difference in LDL-C level between AD patients and healthy controls [9, 10]. The correlation between LDL-C level and AD risk cannot be reliably interpreted in the abovementioned observational studies because these findings may be influenced by potential confounding factors, which is a significant limitation of observational studies. 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)
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