Amyloid-β in Alzheimer’s disease — front and centre after all?

Abstract

The amyloid hypothesis, which proposes that accumulation of the peptide amyloid-β at synapses is the key driver of Alzheimer’s disease (AD) pathogenesis, has been the dominant idea in the field of Alzheimer’s research for nearly 30 years. Recently, however, serious doubts about its validity have emerged, largely motivated by disappointing results from anti-amyloid therapeutics in clinical trials. As a result, much of the AD research effort has shifted to understanding the roles of a variety of other entities implicated in pathogenesis, such as microglia, astrocytes, apolipoprotein E and several others. All undoubtedly play an important role, but the nature of this has in many cases remained unclear, partly due to their pleiotropic functions. Here, we propose that all of these AD-related entities share at least one overlapping function, which is the local regulation of amyloid-β levels, and that this may be critical to their role in AD pathogenesis. We also review what is currently known of the actions of amyloid-β at the synapse in health and disease, and consider in particular how it might interact with the key AD-associated protein tau in the disease setting. There is much compelling evidence in support of the amyloid hypothesis; rather than detract from this, the implication of many disparate AD-associated cell types, molecules and processes in the regulation of amyloid-β levels may lend further support.