As the most common dementia, Alzheimer’s disease (AD) exacts an immense personal, societal, and economic toll. AD was first described at the neuropathological level in the early 1900s. Today, we have mechanistic insight into select aspects of AD pathogenesis and have the ability to clinically detect and diagnose AD and underlying AD pathologies in living patients. These insights demonstrate that AD is a complex, insidious, degenerative proteinopathy triggered by Aβ aggregate formation. Over time Aβ pathology drives neurofibrillary tangle (NFT) pathology, dysfunction of virtually all cell types in the brain, and ultimately, overt neurodegeneration. Yet, large gaps in our knowledge of AD pathophysiology and huge unmet medical need remain. Though we largely conceptualize AD as a disease of aging, heritable and non-heritable factors impact brain physiology, either continuously or at specific time points during the lifespan, and thereby alter risk for devolvement of AD. Herein, I describe the lifelong journey of a healthy brain from birth to death with AD, while acknowledging the many knowledge gaps that remain regarding our understanding of AD pathogenesis. To ensure the current lexicon surrounding AD changes from inevitable, incurable, and poorly manageable to a lexicon of preventable, curable, and manageable we must address these knowledge gaps, develop therapies that have a bigger impact on clinical symptoms or progression of disease and use these interventions at the appropriate stage of disease.

中文翻译：

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阿尔茨海默病——健康大脑进入器官衰竭的旅程

作为最常见的痴呆症，阿尔茨海默病 (AD) 对个人、社会和经济造成巨大损失。AD 在 1900 年代初期首次在神经病理学水平上被描述。今天，我们对 AD 发病机制的某些方面有了机械洞察力，并有能力在临床上检测和诊断 AD 和活体患者的潜在 AD 病理。这些见解表明，AD 是一种由 Aβ 聚集体形成引发的复杂、隐匿、退行性蛋白质病。随着时间的推移，Aβ 病理会导致神经原纤维缠结 (NFT) 病理、大脑中几乎所有细胞类型的功能障碍，并最终导致明显的神经变性。然而，我们在 AD 病理生理学知识和巨大未满足的医疗需求方面仍然存在巨大差距。虽然我们在很大程度上将 AD 概念化为一种衰老疾病，遗传和非遗传因素影响大脑生理，无论是在生命周期中持续地还是在特定时间点，从而改变 AD 恶化的风险。在这里，我描述了一个健康的大脑从出生到 AD 死亡的终生旅程，同时承认在我们对 AD 发病机制的理解方面仍然存在许多知识空白。为了确保当前围绕 AD 的词汇从不可避免、无法治愈和难以管理变为可预防、可治愈和可管理的词汇，我们必须解决这些知识空白，开发对临床症状或疾病进展有更大影响的疗法，并使用这些在疾病的适当阶段进行干预。我描述了患有 AD 的健康大脑从出生到死亡的终生旅程，同时承认在我们对 AD 发病机制的理解方面仍然存在许多知识空白。为了确保当前围绕 AD 的词汇从不可避免、无法治愈和难以管理变为可预防、可治愈和可管理的词汇，我们必须解决这些知识空白，开发对临床症状或疾病进展有更大影响的疗法，并使用这些在疾病的适当阶段进行干预。我描述了患有 AD 的健康大脑从出生到死亡的终生旅程，同时承认在我们对 AD 发病机制的理解方面仍然存在许多知识空白。为了确保当前围绕 AD 的词汇从不可避免、无法治愈和难以管理变为可预防、可治愈和可管理的词汇，我们必须解决这些知识空白，开发对临床症状或疾病进展有更大影响的疗法，并使用这些在疾病的适当阶段进行干预。