Aβ Clearance, 'hub' of Multiple Deficiencies Leading to Alzheimer Disease

The role of the amyloid cascade in the pathogenesis of Alzheimer’s disease (AD) is still the subject of passionate debates (Herrup, 2015; Musiek and Holtzman, 2015). According to quite a radical viewpoint (Herrup, 2015), the tendency to try to find a unifying etiopathogenetic pathway has so far hampered the understanding of such a complex disease. Thus, it would be better to reject the amyloid cascade hypothesis since it is neither necessary nor sufficient to drive the development and progression of AD. Herrup (2015) proposes, as food for thought, to relocate the amyloid cascade in a multifactorial context where it represents only one of a number of deficiencies contributing to degenerative escalation in the age-weakened brain (Herrup, 2015). From a more conservative perspective, the amyloid cascade is the necessary key initiator of a complex sequence of pathological changes, especially tau protein hyperphosphorylation, which mediates neurodegeneration (Musiek and Holtzman, 2015). However, owing to the lapse in time between the appearance of amyloid plaques and that of tau protein tangles, neuronal loss and dementia, as well as the absence of an obvious anatomical colocalization between the amyloidogenic process and neurodegeneration areas, the amyloid cascade hypothesis is not sufficient to explain AD pathology unless supported by a series of “wingmen” (Musiek and Holtzman, 2015).