Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder that is characterized by neurodegeneration, cognitive impairment, and an eventual inability to perform daily tasks. The etiology of Alzheimer’s is complex, with numerous environmental and genetic factors contributing to the disease. Late-onset AD is highly heritable (60 to 80%), and over 40 risk loci for AD have been identified via large genome-wide association studies, most of which are common variants with small effect sizes. Although these discoveries have provided novel insight on biological contributors to AD, disease-modifying treatments remain elusive. Recently, the concepts of resistance to pathology and resilience against the downstream consequences of pathology have been of particular interest in the Alzheimer’s field as studies continue to identify individuals who evade the pathology of the disease even into late life and individuals who have all of the neuropathological features of AD but evade downstream neurodegeneration and cognitive impairment. It has been hypothesized that a shift in focus from Alzheimer’s risk to resilience presents an opportunity to uncover novel biological mechanisms of AD and to identify promising therapeutic targets for the disease. This review will highlight a selection of genes and variants that have been reported to confer protection from AD within the literature and will also discuss evidence for the biological underpinnings behind their protective effect with a focus on genes involved in lipid metabolism, cellular trafficking, endosomal and lysosomal function, synaptic function, and inflammation. Finally, we offer some recommendations in areas where the field can rapidly advance towards precision interventions that leverage the ideas of protection and resilience for the development of novel therapeutic strategies.

中文翻译：

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阿尔茨海默病的保护基因和通路：走向精准干预


阿尔茨海默病 (AD) 是一种进行性神经退行性疾病，其特征是神经退行性变、认知障碍以及最终无法执行日常任务。阿尔茨海默病的病因很复杂，许多环境和遗传因素都会导致这种疾病。晚发性 AD 具有高度遗传性（60% 至 80%），通过大型全基因组关联研究已确定了 40 多个 AD 风险位点，其中大多数是效应量较小的常见变异。尽管这些发现为 AD 的生物学因素提供了新的见解，但缓解疾病的治疗方法仍然难以捉摸。最近，对病理学的抵抗力和对病理学下游后果的恢复力的概念在阿尔茨海默氏病领域引起了特别的兴趣，因为研究不断发现甚至在晚年逃避该疾病病理学的个体以及患有所有神经病理学疾病的个体。 AD 的特征，但避免了下游神经退行性变和认知障碍。据推测，将焦点从阿尔茨海默病风险转向恢复能力，为揭示 AD 的新生物学机制和确定该疾病的有希望的治疗靶点提供了机会。这篇综述将重点介绍文献中报道的可提供 AD 保护的一系列基因和变异体，还将讨论其保护作用背后的生物学基础的证据，重点关注参与脂质代谢、细胞运输、内体和溶酶体功能、突触功能和炎症。 最后，我们在该领域可以迅速推进精准干预的领域提供一些建议，利用保护和恢复力的理念来开发新型治疗策略。