The Amyloid Cascade Hypothesis 2.0: On the Possibility of Once-in-a-Lifetime-Only Treatment for Prevention of Alzheimer’s Disease and for Its Potential Cure at Symptomatic Stages

Abstract

We posit that Alzheimer’s disease (AD) is driven by amyloid-β (Aβ) generated in the amyloid-β protein precursor (AβPP) independent pathway activated by AβPP-derived Aβ accumulated intraneuronally in a life-long process. This interpretation constitutes the Amyloid Cascade Hypothesis 2.0 (ACH2.0). It defines a tandem intraneuronal-Aβ (iAβ)-anchored cascade occurrence: intraneuronally-accumulated, AβPP-derived iAβ triggers relatively benign cascade that activates the AβPP-independent iAβ-generating pathway, which, in turn, initiates the second, devastating cascade that includes tau pathology and leads to neuronal loss. The entire output of the AβPP-independent iAβ-generating pathway is retained intraneuronally and perpetuates the pathway’s operation. This process constitutes a self-propagating, autonomous engine that drives AD and ultimately kills its host cells. Once activated, the AD Engine is self-reliant and independent from Aβ production in the AβPP proteolytic pathway; operation of the former renders the latter irrelevant to the progression of AD and brands its manipulation for therapeutic purposes, such as BACE (beta-site AβPP-cleaving enzyme) inhibition, as futile. In the proposed AD paradigm, the only valid direct therapeutic strategy is targeting the engine’s components, and the most effective feasible approach appears to be the activation of BACE1 and/or of its homolog BACE2, with the aim of exploiting their Aβ-cleaving activities. Such treatment would collapse the iAβ population and ‘reset’ its levels below those required for the operation of the AD Engine. Any sufficiently selective iAβ-depleting treatment would be equally effective. Remarkably, this approach opens the possibility of a short-duration, once-in-a-lifetime-only or very infrequent, preventive or curative therapy for AD; this therapy would be also effective for prevention and treatment of the ‘common’ pervasive aging-associated cognitive decline. The ACH2.0 clarifies all ACH-unresolved inconsistencies, explains the widespread ‘resilience to AD’ phenomenon, predicts occurrences of a category of AD-afflicted individuals without excessive Aβ plaque load and of a novel type of familial insusceptibility to AD; it also predicts the lifespan-dependent inevitability of AD in humans if untreated preventively. The article details strategy and methodology to generate an adequate AD model and validate the hypothesis; the proposed AD model may also serve as a research and drug development platform.

Characterization of Orange Peel Extract and Its Potential Protective Effect against Aluminum Chloride-Induced Alzheimer’s Disease

“…The amyloid cascade hypothesis proposed that the key clinical hallmarks of Alzheimer’s disease were extracellular deposits of A peptides as senile plaques, intraneuronal neurofibrillary tangles (NFTs), and extensive neuronal death [ 49 , 50 ]. Therefore, Aβ peptides have dominated new therapeutic research over the past twenty years as a possible target for AD [ 51 ].…”

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

“…The causative role of iAβ is the central tenet of the ACH2.0, which envisions AD as a two-stage disease. In the first, asymptomatic stage, AβPP-derived Aβ accumulates, in a decades-long process, to critical levels that cause the activation of the second, devastating AD stage that is anchored and driven by an agent which is independent of AβPP and which sustains and perpetuates its own production [1,2]. In terms of the ACH2.0, this agent is iAβ generated in the AβPP-independent pathway [1].…”

“…In the first, asymptomatic stage, AβPP-derived Aβ accumulates, in a decades-long process, to critical levels that cause the activation of the second, devastating AD stage that is anchored and driven by an agent which is independent of AβPP and which sustains and perpetuates its own production [1,2]. In terms of the ACH2.0, this agent is iAβ generated in the AβPP-independent pathway [1]. Potentially, as discussed in [2], the agent driving the stage two of AD can be other than iAβ.…”

“…But even this narrow commonality is rather superficial: whereas in the ACH, AD is caused by extracellular Aβ produced and secreted in the Aβ protein precursor (AβPP)-proteolytic pathway, in the ACH2.0, the disease is triggered by AβPP-derived intraneuronal Aβ (iAβ) accumulated to sufficient levels and is driven by iAβ generated independently of AβPP. The rationale for the ACH2.0, as well as its various aspects, has been discussed in detail elsewhere [1][2][3]. The present discourse takes the preceding studies as the established point of departure.…”

“…To better orient the reader, the following few sections (Sections 2-6), preceding the analysis of the dynamics of iAβ accumulation, briefly summarize four main principles of the ACH 2.0 (for detailed description and analysis see [1,2]). They are: (1)-AD and AACD are caused and driven by intra-rather than extracellular Aβ; (2)-AD (but not AACD) is a two-stage disease; (3)-the symptomatic second stage of AD is driven by iAβ produced in the AβPP-independent pathway; (4)-iAβ generated independently of AβPP is retained intraneuronally, perpetuates its own production and renders AβPP-derived iAβ irrelevant for the progression of AD due to its marginal (in comparison with iAβ produced independently of AβPP) contribution into the cellular iAβ pool.…”