The natural and molecular history of Alzheimer's disease.

Alzheimer's disease (AD) is a very frequent brain pathology of the elderly, with an etiology by far more complicated than thought in the nineties. In particular, the complexity comes from the coexistence of two degenerating processes, tau aggregation and Abeta deposition, that affect polymodal association brain areas, a feature never observed in non-human primates and difficult to model. Genetic studies have shown that AbetaPP plays a central role in familial and sporadic AD, but the role of tau has been for a long time understated. To apprehend this role, we have developed a spatio-temporal analysis of tauopathy in many brain areas of hundreds of non-demented and demented patients. This prospective and multidisciplinary study showed us that tauopathy always progresses in the brain along a very precise and invariable pathway, from the entorhinal then hippocampal formation to polymodal association areas to end in primary regions and in many subcortical areas. The cognitive impairment follows exactly the progression of the affected brain regions. In strict parallelism, neocortical Abeta deposits increase in quantity and heterogeneity, suggesting a direct link between both neurodegenerative processes. Altogether, our molecular study suggests that AD is a tauopathy fueled by AbetaPP dysfunction. Restoring AbetaPP loss of function seems to be the most efficient therapeutic approach.