The Amyloid Cascade Hypothesis 2.0 for Alzheimer's Disease and Aging-Associated Cognitive Decline: From Molecular Basis to Effective Therapy

With the long-standing amyloid cascade hypothesis (ACH) largely discredited, there is an acute need for a new all-encompassing interpretation of Alzheimer's disease (AD). Whereas such a recently proposed theory of AD is designated ACH2.0, its commonality with the ACH is limited to the recognition of the centrality of amyloid-β (Aβ) in the disease, necessitated by the observation that AD-causing mutations affect, in one way or another, Aβ. Yet, even this narrow commonality is superficial since AD-causing Aβ of the ACH differs distinctly from that specified in the ACH2.0: Whereas in the former, the disease is caused by secreted extracellular Aβ, in the latter, it is triggered by Aβ-protein-precursor (AβPP)-derived Aβ ( Aβ) and driven by Aβ generated of AβPP. The ACH2.0 envisions AD as a two-stage disorder. The first, asymptomatic stage is a decades-long accumulation of AβPP-derived Aβ, which occurs via internalization of secreted Aβ and through intracellular retention of a fraction of Aβ produced by AβPP proteolysis. When AβPP-derived Aβ reaches critical levels, it activates a self-perpetuating AβPP-independent production of Aβ that drives the second, devastating AD stage, a cascade that includes tau pathology and culminates in neuronal loss. The present study analyzes the dynamics of Aβ accumulation in health and disease and concludes that it is the prime factor driving both AD and aging-associated cognitive decline (AACD). It discusses mechanisms potentially involved in AβPP-independent generation of Aβ, provides mechanistic interpretations for all principal aspects of AD and AACD including the protective effect of the Icelandic AβPP mutation, the early onset of FAD and the sequential manifestation of AD pathology in defined regions of the affected brain, and explains why current mouse AD models are neither adequate nor suitable. It posits that while drugs affecting the accumulation of AβPP-derived Aβ can be effective only protectively for AD, the targeted degradation of Aβ is the best therapeutic strategy for both prevention and effective treatment of AD and AACD. It also proposes potential Aβ-degrading drugs.