Genetic factors play a major role in Alzheimer's disease (AD) pathology, but biological mechanisms through which these factors contribute to AD remain elusive. Using a cerebrospinal fluid (CSF) proteomic approach, we examined associations between polygenic risk scores for AD (PGRS) and CSF proteomic profiles in 250 individuals with normal cognition, mild cognitive impairment, and AD-type dementia from the Alzheimer's Disease Neuroimaging Initiative. Out of 412 proteins, 201 were associated with PGRS. Hierarchical clustering analysis on proteins associated with PGRS at different single-nucleotide polymorphism p-value inclusion thresholds identified 3 clusters: (1) a protein cluster correlated with highly significant single-nucleotide polymorphisms, associated with amyloid-beta pathology and complement cascades; (2) a protein cluster associated with PGRS additionally including variants contributing to modest risk, involved in neural injury; (3) a protein cluster that also included less strongly associated variants, enriched with cytokine-cytokine interactions and cell adhesion molecules. These findings suggest that CSF protein levels reflect varying degrees of genetic liability for AD and may serve as a tool to investigate biological mechanisms in AD.

中文翻译：

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与脑脊液中特定蛋白质组学特征相关的阿尔茨海默病的遗传责任程度

遗传因素在阿尔茨海默病 (AD) 病理学中起主要作用，但这些因素导致 AD 的生物学机制仍然难以捉摸。使用脑脊液 (CSF) 蛋白质组学方法，我们检查了 250 名认知正常、轻度认知障碍和阿尔茨海默病神经影像学倡议的 AD 型痴呆患者的 AD 多基因风险评分 (PGRS) 与脑脊液蛋白质组学特征之间的关联。在 412 种蛋白质中，201 种与 PGRS 相关。在不同单核苷酸多态性 p 值包含阈值下对与 PGRS 相关的蛋白质进行分层聚类分析，确定了 3 个簇：（1）与高度显着的单核苷酸多态性相关的蛋白质簇，与淀粉样蛋白 β 病理学和补体级联相关；(2) 与 PGRS 相关的蛋白质簇还包括导致中等风险的变异，涉及神经损伤；(3) 一个蛋白质簇，还包括不太强相关的变体，富含细胞因子-细胞因子相互作用和细胞粘附分子。这些发现表明 CSF 蛋白水平反映了 AD 不同程度的遗传责任，并可作为研究 AD 生物学机制的工具。