The history of the cholinergic hypothesis.

The cholinergic hypothesis of cognitive impairment and Alzheimer's disease has been for decades a "polar star" for studies on dementia and neurodegenerative diseases. Aim of the present article is to briefly summarize its birth and its evolution throughout years and discoveries. Putting the cholinergic hypothesis in an historical perspective, allows to appreciate the enormous amount of experimental and clinical research that it has stimulated over years and the impressive extent of knowledge generated by this research. While some of the assumptions at the basis of its original formulation are disputable in the light of recent developments, the cholinergic hypothesis has, however, constituted an invaluable stimulus to better understand not only the anatomy and the biochemistry of the cholinergic systems of brain connections but also its developmental biology, its complex relationships with trophic factors, its role in cognitive functions. Thus, rather than being consigned to history, the cholinergic hypothesis will likely contribute to further understanding dementia and neurodegenerative diseases and will hopefully be integrated in novel therapies and treatments.