Pantel Johannes
Arbeitsbereich Altersmedizin, Institut für Allgemeinmedizin, Goethe-Universität, Theodor-Stern-Kai 7, 60590, Frankfurt a. M., Deutschland.
Z Gerontol Geriatr. 2017 Oct;50(7):576-587. doi: 10.1007/s00391-017-1307-2. Epub 2017 Sep 18.
The present article aims to provide a short overview of the discovery history, conceptual development, as well as on current neurobiological and pharmacological research questions in the field of Alzheimer's disease (AD). In view of the long hoped for but so far unachieved therapeutic breakthrough, this also includes a critical reflection of current research paradigms.
Starting from the first case report described by Alois Alzheimer in 1906, the historical impact of his seminal discovery is reconstructed. Neurobiological research paradigms central to AD are discussed with respect to their relevance for modern biomarker-based diagnostic approaches as well as to the development of innovative disease-modifying drug therapies.
Originally conceived as a rare presenile form of dementia it was not until the 1970s that AD was granted an orphan disease status. The biomedical deconstruction of senility and the introduction of new research methods enabled the nosological unification of AD with the concept of senile dementia which, in turn led to a global flowering of AD research. In the 1990s the amyloid cascade hypothesis was introduced as the leading research paradigm of AD. In the following years this stimulated the development of a huge variety of innovative biomarker-based diagnostic and disease-modifying pharmacological approaches.
Against the background of the recent failures of many clinical drug trials, the relevance of the amyloid cascade hypothesis to explain the etiology of sporadic AD is increasingly being questioned. On the one hand, this leaves the question of the central etiological paradigm unresolved and on the other hand it stimulated a debate on alternative etiological models which might lead to fruitful consequences for future research strategies.
本文旨在简要概述阿尔茨海默病（AD）领域的发现历史、概念发展以及当前的神经生物学和药理学研究问题。鉴于人们长期以来一直期待但至今尚未实现治疗突破，本文还对当前的研究范式进行了批判性反思。
从1906年阿洛伊斯·阿尔茨海默描述的首例病例报告开始，重构了他这一开创性发现的历史影响。讨论了AD核心的神经生物学研究范式与基于现代生物标志物的诊断方法的相关性，以及与创新的疾病修饰药物疗法发展的相关性。
AD最初被认为是一种罕见的早老性痴呆形式，直到20世纪70年代才被认定为罕见病。衰老的生物医学解构以及新研究方法的引入，使AD与老年痴呆症的概念在疾病分类学上得以统一，进而促使AD研究在全球蓬勃发展。20世纪90年代，淀粉样蛋白级联假说被引入作为AD的主要研究范式。在随后的几年里，这刺激了大量基于创新生物标志物的诊断和疾病修饰药理学方法的发展。
在近期许多临床药物试验失败的背景下，淀粉样蛋白级联假说解释散发性AD病因的相关性受到越来越多的质疑。一方面，这使得核心病因范式的问题悬而未决；另一方面，它引发了关于替代病因模型的争论，这可能会给未来的研究策略带来丰硕成果。
