[Alzheimer's disease from Auguste Deter to the present : Progress, disappointments and open questions].

aimThe 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. MATERIAL AND

methodsStarting 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.

resultsOriginally 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.

conclusionAgainst 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.