Twenty-five years of the amyloid hypothesis of Alzheimer’s disease: Advances, failures and new perspectives

Abstract

Amyloid hypothesis of Alzheimer’s disease (AD) has been long the primary one. During the 25-year history the concept has been dramatically changed. Accumulation of β-amyloid is associated not only with the disruption of its synthesis (as it seemed after the discovery of genetic mechanisms of some familial cases of AD) but rather with the disruption of its clearance and elimination from the brain tissue via the microcirculatory system. It has been recognized that soluble oligomers of β-amyloid, but not senile plaques that consisted of insoluble conjugates described by A. Alzheimer 100 years ago, play a key pathogenic role in the brain. Interrelation of vascular and degenerative processes is confirmed by common risk factors, clinical, neuroimaging, pathomorphological and experimental data. Insulin-resistance is also one of the links between AD degenerative and vascular processes. Based on the current state of the amyloid hypothesis, perspectives of new multimodal treatment strategies are discussed.