Genetic, animal and epidemiological studies involving biomolecular and clinical endophenotypes implicate mitochondrial dysfunction in Alzheimer's disease (AD) pathogenesis. Polygenic risk scores (PRS) provide a novel approach to assess biological pathway-associated disease risk by combining the effects of variation at multiple, functionally related genes. We investigated the associations of PRS for genes involved in 12 mitochondrial pathways (pathway-PRS) with AD in 854 participants from Alzheimer's Disease Neuroimaging Initiative. Pathway-PRS for the nuclear-encoded mitochondrial genome (OR: 1.99 [95% Cl: 1.70, 2.35]) and three mitochondrial pathways is significantly associated with increased AD risk: (i) response to oxidative stress (OR: 2.01 [95% Cl: 1.71, 2.38]); (ii) mitochondrial transport (OR: 1.81 [95% Cl: 1.55, 2.13]); (iii) hallmark oxidative phosphorylation (OR: 1.22 [95% Cl: 1.06, 1.40]. Therapeutic approaches targeting these pathways may have the potential for modifying AD pathogenesis. Further investigation is required to establish a causal role for these pathways in AD pathology.

涉及生物分子和临床内表型的遗传、动物和流行病学研究表明阿尔茨海默病 (AD) 发病机制中的线粒体功能障碍。多基因风险评分 (PRS) 通过结合多个功能相关基因的变异效应，提供了一种评估生物通路相关疾病风险的新方法。我们在阿尔茨海默病神经影像学计划的 854 名参与者中调查了 PRS 与 12 种线粒体途径 (pathway-PRS) 相关基因与 AD 的关联。核编码线粒体基因组的通路-PRS (OR: 1.99 [95% Cl: 1.70, 2.35]) 和三个线粒体通路与 AD 风险增加显着相关：(i) 对氧化应激的反应 (OR: 2.01 [95%氯：1.71，2.38]）；(ii) 线粒体转运 (OR: 1.81 [95% Cl: 1.55, 2.13]);