Alzheimer’s disease (AD) is a fatal disease that threatens the quality of life of an aging population at a global scale. Various hypotheses on the etiology of AD have been developed over the years to guide efforts in search of therapeutic strategies. In this review, we focus on four AD hypotheses currently relevant to AD onset: the prevailing amyloid cascade hypothesis, the well-recognized tau hypothesis, the increasingly popular pathogen (viral infection) hypothesis, and the infection-related antimicrobial protection hypothesis. In briefly reviewing the main evidence supporting each hypothesis and discussing the questions that need to be addressed, we hope to gain a better understanding of the complicated multi-layered interactions in potential causal and/or risk factors in AD pathogenesis. As a defining feature of AD, the existence of amyloid deposits is likely fundamental to AD onset but is insufficient to wholly reproduce many complexities of the disorder. A similar belief is currently also applied to hyperphosphorylated tau aggregates within neurons, where tau has been postulated to drive neurodegeneration in the presence of pre-existing Aβ plaques in the brain. Although infection of the central nerve system by pathogens such as viruses may increase AD risk, it is yet to be determined whether this phenomenon is applicable to all cases of sporadic AD and whether it is a primary trigger for AD onset. Lastly, the antimicrobial protection hypothesis provides insight into a potential physiological role for Aβ peptides, but how Aβ/microbial interactions affect AD pathogenesis during aging awaits further validation. Nevertheless, this hypothesis cautions potential adverse effects in Aβ-targeting therapies by hindering potential roles for Aβ in anti-viral protection. AD is a multi-factor complex disorder, which likely requires a combinatorial therapeutic approach to successfully slow or reduce symptomatic memory decline. A better understanding of how various causal and/or risk factors affecting disease onset and progression will enhance the likelihood of conceiving effective treatment paradigms, which may involve personalized treatment strategies for individual patients at varying stages of disease progression.

中文翻译：

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阿尔茨海默病中的淀粉样蛋白、tau蛋白、病原体感染和抗菌保护——AD发病机制的顺从者、非顺从者和现实前景


阿尔茨海默病（AD）是一种致命疾病，威胁着全球范围内老龄化人口的生活质量。多年来，人们已经提出了关于 AD 病因的各种假设，以指导寻找治疗策略的努力。在这篇综述中，我们重点关注目前与 AD 发病相关的四种 AD 假说：普遍存在的淀粉样蛋白级联假说、公认的 tau 假说、日益流行的病原体（病毒感染）假说以及感染相关的抗菌保护假说。通过简要回顾支持每个假设的主要证据并讨论需要解决的问题，我们希望更好地了解 AD 发病机制中潜在因果和/或危险因素中复杂的多层次相互作用。作为 AD 的一个决定性特征，淀粉样蛋白沉积物的存在可能是 AD 发病的基础，但不足以完全重现该疾病的许多复杂性。目前，类似的观点也适用于神经元内过度磷酸化的 tau 蛋白聚集体，假设大脑中存在 Aβ 斑块时，tau 蛋白会驱动神经退行性变。尽管病毒等病原体感染中枢神经系统可能会增加 AD 风险，但尚未确定这种现象是否适用于所有散发性 AD 病例以及是否是 AD 发病的主要触发因素。最后，抗菌保护假说提供了对 Aβ 肽潜在生理作用的深入了解，但 Aβ/微生物相互作用如何影响衰老过程中的 AD 发病机制还有待进一步验证。然而，这一假说通过阻碍 Aβ 在抗病毒保护中的潜在作用来警告 Aβ 靶向治疗的潜在副作用。 AD 是一种多因素复杂性疾病，可能需要组合治疗方法才能成功减缓或减少症状性记忆衰退。更好地了解影响疾病发作和进展的各种因果和/或风险因素将提高构思有效治疗范例的可能性，这可能涉及针对处于疾病进展不同阶段的个体患者的个性化治疗策略。