Alzheimer’s disease (AD) is a multifactorial disease that affects more than 5 million Americans. Multiple pathways might be involved in the AD pathogenesis. The implication of lipid genetic susceptibility on brain gene expression is yet to be investigated. The current study included 192 brain samples from AD patients who were enrolled in the ROSMAP study. The samples were genotyped and imputed to the HRC Reference Panel. Lipid polygenetic risk score was constructed from the weighted sum of genetic variants associated with low-density lipoprotein cholesterol (LDL-C). The gene expression was profiled by RNA sequencing, and the association of gene expression with lipid polygenetic risk scores was tested by linear regression models adjusted for age, sex and APOE e4 alleles. Three genes were found to associate with lipid polygenetic risk scores, including HMCN2 (P = 3.6 × 10^–7), PDLIM5 (P = 1.2 × 10^–6), and FHL5 (P = 2.0 × 10^–6). Network analysis revealed multiple related pathways, including dopaminergic synapse (P = 4.5 × 10^–5), circadian entrainment (P = 1.1 × 10^–4), and cholinergic synapse (P = 2.3 × 10^–4). Our study underscores the importance of lipid regulation and metabolism to AD heterogeneity.

阿尔茨海默病 (AD) 是一种多因素疾病，影响超过 500 万美国人。 AD 发病机制可能涉及多种途径。脂质遗传易感性对大脑基因表达的影响仍有待研究。当前的研究包括来自参加 ROSMAP 研究的 AD 患者的 192 个大脑样本。对样本进行基因分型并归入 HRC 参考小组。脂质多基因风险评分是根据与低密度脂蛋白胆固醇 (LDL-C) 相关的遗传变异的加权和构建的。通过 RNA 测序分析基因表达，并通过针对年龄、性别和 APOE e4 等位基因进行调整的线性回归模型测试基因表达与脂质多基因风险评分的关联。发现三个基因与脂质多遗传风险评分相关，包括HMCN2 ( P = 3.6 × 10 ^–7 )、 PDLIM5 ( P = 1.2 × 10 ^–6 ) 和FHL5 ( P = 2.0 × 10 ^–6 )。网络分析揭示了多种相关途径，包括多巴胺能突触 ( P = 4.5 × 10 ^–5 )、昼夜节律夹带 ( P = 1.1 × 10 ^–4 ) 和胆碱能突触 ( P = 2.3 × 10 ^–4 )。我们的研究强调了脂质调节和代谢对 AD 异质性的重要性。