Genetic evidence for the liver-brain axis: lipid metabolism and neurodegenerative disease risk

作者：Zeyu Wang, Zixiao Yin, Guangyong Sun, Dong Zhang, Jianguo Zhang · 发表于：Lipids in Health and Disease · 年份：2025 · DOI：10.1186/s12944-025-02455-3 · 被引用次数：16 · 研究领域：Amyotrophic Lateral Sclerosis Research、Multiple Sclerosis Research Studies、Alzheimer's disease research and treatments

The liver‒brain axis is critical in neurodegenerative diseases (NDs), with lipid metabolism influencing neuroinflammation and microglial function. A systematic investigation of the genetic relationship between lipid metabolism abnormalities and ND, namely, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), is lacking. To assess potential causal links between ND and six lipid parameters, two-sample Mendelian randomization (MR) was used. Large-scale European ancestry GWAS data for lipid parameters and ND (AD, ALS, PD, and MS) were used. Genetic variants demonstrating significant correlations ( P < 5 × 10 −8 ) with lipid metabolism parameters were identified and employed as instrumental variables (IVs) after proper validation. The research incorporated UK Biobank genomic data to examine associations between genetic variants and lipid metabolism parameters. The analysis included primary MR, sensitivity analyses, and multivariable MR, which considered potential mediators. MR via the inverse-variance weighted method revealed causal effects of cholesterol (CHOL, OR = 1.10, 95% CI: 1.03–1.18, P = 4.23 × 10⁻ 3 ) and low-density lipoprotein cholesterol (LDLC, OR = 1.10, 95% CI: 1.03–1.17, P = 3.28 × 10⁻ 3 ) on the risk of ALS, which were validated across multiple methods. Potential correlations were observed between ApoB and ALS and inversely correlated with AD, whereas no significant associations were found for PD or M...