Amyloid-beta in Alzheimer's disease: the horse or the cart? Pathogenic or protective?

While the pathogenesis of Alzheimer's disease (AD) is unclear, amyloid-beta plaques remain major lesions in the brain of individuals with AD. Likewise, amyloid-beta is one of the best-studied proteins relating to the pathogenesis of AD. Indeed, the pathological diagnosis of AD tends to be congruous with the quantity of amyloid-beta. However, it is important to recognize that pathological diagnosis merely represents the association of a pattern of pathological changes with a clinical phenotype. Therefore, it should be acknowledged that, although amyloid-beta detection and semiquantification have some diagnostic utility, the simple presence of amyloid plaques, as with proteinaceous accumulations in essentially all neurodegenerative diseases, does not presume aetiology. Thus, in this review, we discuss the role of amyloid-beta in the pathogenesis of AD and provide an alternative view to the widely accepted dogma.