Most neurodegenerative diseases are proteinopathies, which are characterized by the aggregation of misfolded proteins. Although many proteins have an intrinsic propensity to aggregate, particularly when cellular clearance systems start to fail in the context of ageing, only a few form fibrillar aggregates. In Alzheimer disease, the peptide amyloid-β (Aβ) and the protein tau aggregate to form plaques and tangles, respectively, which comprise the histopathological hallmarks of this disease. This Review discusses the complexity of Aβ biogenesis, trafficking, post-translational modifications and aggregation states. Tau and its various isoforms, which are subject to a vast array of post-translational modifications, are also explored. The methodological advances that revealed this complexity are described. Finally, the toxic effects of distinct species of tau and Aβ are discussed, as well as the concept of protein 'strains', and how this knowledge can facilitate the development of early disease biomarkers for stratifying patients and validating new therapies. By targeting distinct species of Aβ and tau for therapeutic intervention, the way might be paved for personalized medicine and more-targeted treatment strategies.

大多数神经退行性疾病是蛋白病，其特征在于错误折叠的蛋白质的聚集。尽管许多蛋白质具有固有的聚集倾向，尤其是当细胞清除系统在衰老的情况下开始失效时，只有少数形成纤维状聚集体。在阿尔茨海默氏病中，肽淀粉样蛋白-β（Aβ）和蛋白tau分别聚集形成斑块和缠结，构成该疾病的组织病理学特征。这篇评论讨论了Aβ生物发生，运输，翻译后修饰和聚集状态的复杂性。还探讨了Tau及其各种同工型，它们受到大量翻译后修饰的影响。描述了揭示这种复杂性的方法学进展。最后，讨论了不同种类的tau和Aβ的毒性作用，以及蛋白质“菌株”的概念，并讨论了该知识如何促进早期疾病生物标记物的开发，从而对患者进行分层并验证新疗法。通过针对不同种类的Aβ和tau进行治疗干预，可能为个性化医学和更具针对性的治疗策略铺平了道路。