Weaver Donald F
Krembil Research Institute, University Health Network, Departments of Medicine, Chemistry, Pharmaceutical Sciences, University of Toronto, Toronto, ON M5T 0S8, Canada.
Brain Sci. 2023 Dec 31;14(1):41. doi: 10.3390/brainsci14010041.
One of the major obstacles confronting the formulation of a mechanistic understanding for Alzheimer's disease (AD) is its immense complexity-a complexity that traverses the full structural and phenomenological spectrum, including molecular, macromolecular, cellular, neurological and behavioural processes. This complexity is reflected by the equally complex diversity of risk factors associated with AD. However, more than merely mirroring disease complexity, risk factors also provide fundamental insights into the aetiology and pathogenesis of AD as a neurodegenerative disorder since they are central to disease initiation and subsequent propagation. Based on a systematic literature assessment, this review identified 30 risk factors for AD and then extended the analysis to further identify neuroinflammation as a unifying mechanism present in all 30 risk factors. Although other mechanisms (e.g., vasculopathy, proteopathy) were present in multiple risk factors, dysfunction of the neuroimmune-neuroinflammation axis was uniquely central to all 30 identified risk factors. Though the nature of the neuroinflammatory involvement varied, the activation of microglia and the release of pro-inflammatory cytokines were a common pathway shared by all risk factors. This observation provides further evidence for the importance of immunopathic mechanisms in the aetiopathogenesis of AD.
对阿尔茨海默病（AD）形成机制理解的主要障碍之一是其极其复杂——这种复杂性贯穿了整个结构和现象学范围，包括分子、大分子、细胞、神经和行为过程。与AD相关的风险因素同样复杂多样，这反映了这种复杂性。然而，风险因素不仅反映了疾病的复杂性，还为AD作为一种神经退行性疾病的病因和发病机制提供了基本见解，因为它们是疾病起始和后续发展的核心。基于系统的文献评估，本综述确定了30个AD风险因素，然后进一步扩展分析，以确定神经炎症是所有30个风险因素中存在的统一机制。虽然其他机制（如血管病变、蛋白病变）在多个风险因素中存在，但神经免疫-神经炎症轴功能障碍是所有30个已确定风险因素的独特核心。尽管神经炎症参与的性质各不相同，但小胶质细胞的激活和促炎细胞因子的释放是所有风险因素共有的常见途径。这一观察结果为免疫病理机制在AD病因发病机制中的重要性提供了进一步证据。
