Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
Rheumatology and Immunology Department, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
Front Endocrinol (Lausanne). 2024 Sep 19;15:1456005. doi: 10.3389/fendo.2024.1456005. eCollection 2024.
Lewy body dementia (LBD) is a neurodegenerative disorder characterized by the accumulation of Lewy bodies, which primarily composed of misfolded alpha-synuclein (αS). The development of LBD and APOE4 subtypes is thought to be associated with disorders of lipid metabolism. In this study, we investigated the causal relationship between serum lipids, liposomes and LBD using a two-sample Mendelian randomization (TSMR) method.
A TSMR analysis of genome-wide association study (GWAS) data for 8 serum lipids, 179 lipidomes components, LBD and its subtypes was performed, using inverse variance weighted as the primary outcome. To ensure robustness, the sensitivity analyses including MR Pleiotropy RESidual Sum and Outlier, Cochran's test, leave-one-out method and funnel plots were performed.
In this study, we found that low-density lipoprotein cholesterol (LDL-C) (OR=1.45, 95% CI=1.19-1.77, P<0.001) and remnant cholesterol (RC) (OR=2.64, 95% CI=1.64-4.28, P<0.001) had significant positive causal effects on LBD, and RC also had a positive effect on LBD in carriers of the APOE4 gene. The results of lipidome analysis showed that phosphatidylcholine (PC) (O-16:0_20:4) levels (OR=0.86, 95% CI=0.75-0.98, P=0.02) and PC (O-18:1_20:4) levels (OR=0.76, 95% CI=0.65-0.89, P <0.001) had negative causal effects on LBD, whereas phosphatidylinositol (PI) (18:1_20:4) levels had a positive causal effect on LBD (OR=1.19, 95% CI=1.02-1.39, P=0.03). For LBD with APOE4 carriers, high levels of PC (16:1_18:0) and PC (O-18:2_18:1) had a significant positive effect, while high levels of PC (O-16:1_18:0), phosphatidylethanolamine (PE) (O-18:2_18:1), sphingomyelin (SM) (d38:2), and triacylglycerol (TAG) (56:5) significantly reduced the risk. No heterogeneity and horizontal pleiotropy were observed in sensitivity analysis.
Elevated LDL-C and RC levels are significant risk factors for LBD, with RC also impacting APOE4-carrying LBD. Glycerophospholipids play a crucial role in the pathogenesis of LBD, but the specific components that play a role differ from those with the APOE4 carries. These findings highlight the importance of lipid metabolism in LBD and APOE4 subtypes.
路易体痴呆（LBD）是一种以路易体积累为特征的神经退行性疾病，路易体主要由错误折叠的α-突触核蛋白（αS）组成。LBD 和 APOE4 亚型的发展被认为与脂代谢紊乱有关。在这项研究中，我们使用两样本 Mendelian 随机化（TSMR）方法研究了血清脂质、脂质体与 LBD 之间的因果关系。
使用逆方差加权作为主要结果，对 8 种血清脂质、179 种脂质组成分、LBD 及其亚型的全基因组关联研究（GWAS）数据进行 TSMR 分析。为确保稳健性，进行了敏感性分析，包括 MR 多效性残留和异常值、Cochran 检验、逐一排除法和漏斗图。
在这项研究中，我们发现低密度脂蛋白胆固醇（LDL-C）（OR=1.45，95%CI=1.19-1.77，P<0.001）和残余胆固醇（RC）（OR=2.64，95%CI=1.64-4.28，P<0.001）对 LBD 有显著的正向因果关系，RC 对携带 APOE4 基因的 LBD 也有正向影响。脂质组分析结果表明，磷脂酰胆碱（PC）（O-16:0_20:4）水平（OR=0.86，95%CI=0.75-0.98，P=0.02）和 PC（O-18:1_20:4）水平（OR=0.76，95%CI=0.65-0.89，P<0.001）对 LBD 有负向因果关系，而磷脂酰肌醇（PI）（18:1_20:4）水平对 LBD 有正向因果关系（OR=1.19，95%CI=1.02-1.39，P=0.03）。对于携带 APOE4 的 LBD 患者，高水平的 PC（16:1_18:0）和 PC（O-18:2_18:1）有显著的正向作用，而高水平的 PC（O-16:1_18:0）、磷脂酰乙醇胺（PE）（O-18:2_18:1）、鞘磷脂（SM）（d38:2）和三酰甘油（TAG）（56:5）则显著降低了风险。在敏感性分析中未观察到异质性和水平多效性。
升高的 LDL-C 和 RC 水平是 LBD 的显著危险因素，RC 也会影响携带 APOE4 的 LBD。甘油磷脂在 LBD 的发病机制中起着至关重要的作用，但发挥作用的具体成分与携带 APOE4 的患者不同。这些发现强调了脂代谢在 LBD 和 APOE4 亚型中的重要性。
