Developing Alzheimer's disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (I) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N=1,895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N=1,654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N=293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p<0.05). The pathway that contributed most to the overall modulation of AD-risk was β-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p<0.05), while specifically immune response (p=0.003) and endocytosis (p=0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to β-amyloid metabolism.

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免疫反应和内吞途径与抗阿尔茨海默氏病相关

阿尔茨海默氏病（AD）的发展受五个主要AD途径中涉及的多种遗传变异的影响。对于每个人而言，这些途径可能会不同程度地导致AD风险的改变。参与的途径弹性对AD迄今为止，已经不好解决。在这里，我们调查了每种分子机制在多大程度上与（I）AD风险增加和（ii）弹性相关通过比较特定于途径的多基因风险评分（pathway-PRS）来对抗AD直至极端高龄。我们使用了与AD相关的29个遗传变异来开发AD中涉及的五个主要途径的PRS途径。我们开发了一个集成框架，该框架允许多个基因与一个变体关联，以及多个途径与一个基因关联。我们在表型良好的AD患者的阿姆斯特丹痴呆症队列（N = 1,895），阿姆斯特丹纵向老龄化研究阿姆斯特丹（N = 1,654）和我们独特的100多个避免了认知健康的百岁老人的研究队列中研究了PRS途径AD（N ＝ 293）。最后，我们估算了普通人群中每种途径对AD遗传风险的贡献。p＜0.05）。对AD风险的整体调节作用最大的途径是β-淀粉样蛋白代谢（29.6％），其主要由APOE变异驱动。排除APOE变体后，所有途径PRS均与AD风险增加相关（除了血管生成，p <0.05），而特异性免疫应答（p = 0.003）和胞吞作用（p = 0.0003）与对AD的抵抗力相关。实际上，后两种途径的变体已成为AD遗传风险总体调节的主要贡献者（分别为45.5％和19.2％）。与弹性相关的遗传变异针对AD的研究表明直至极端年龄之前，哪些途径与维持认知功能有关。我们的工作表明，良好的免疫反应和维持的胞吞途径可能与一般的神经保护有关，这突显了除了β淀粉样蛋白代谢外，还需要研究这些途径。