The underexplored question of β-amyloid monomers.

Conceived more than 25 years ago, the amyloid cascade hypothesis of Alzheimer's disease has evolved to accommodate new findings, namely different forms of β-amyloid aggregates and downstream dysfunctions. Yet, the cascade does not mention its very beginning, the β-amyloid monomer. Here, I will discuss the monomer from a functional evolutionary perspective, highlighting the potential advantages of a native unfolded state that, however, involves an amyloidogenic risk. Finally, I will make a summary of what is known about its functional role in the brain and discuss the implications of its conceivable shortage in the development of Alzheimer's disease.