Is the slow amyloid-β aggregation, occurring for years prior to the onset of evident symptoms, really the cause of Alzheimer’s disease? The amyloid cascade hypothesis suggests that this accumulation of misfolded amyloid-β, and the toxic biochemistry surrounding its aggregates, set the stage for the much more severe later stage of Alzheimer’s disease, in which neuroinflammation and tau aggregation kill neurons – and ultimately the patient. The hypothesis makes sense given what is known of the relevant biochemistry, but has been strongly challenged by (a) the great difficulty in clearing amyloid-β from the brain, a project that took decades to produce successful therapies, and (b) that successful clearance has failed to produce meaningful patient benefits.
The biochemistry of the brain is exceptionally complex, and the failure of amyloid-β clearance to help patients may not in fact imply that the amyloid cascade hypothesis is very wrong. “Very wrong” in this context could mean that, for example, the aggregation of amyloid-β is a side-effect, a consequence of other processes that actually drive the onset of Alzheimer’s, and thus targeting it will never prove to be useful. Or it could mean that while amyloid-β is a meaningful component of the condition, it is not sufficient to clear it without also repairing the vasculature, or removing senescent cells, or damping down neuroinflammation. However, it may also be the case that amyloid-β is in fact a useful target, and the failure to help patients occurred because the wrong forms or localizations of amyloid-β were targeted, or that patients were treated too late in the progression of Alzheimer’s disease, after a point at which amyloid-β became irrelevant.
Biochemistry is complicated! Researchers have devoted a great deal of thought in recent years to amending the amyloid cascade hypothesis in ways that could explain the failure of successful clearance to help patients. Today’s open access paper is one example of a modified amyloid cascade hypothesis, an attempt to reconcile what is known into a unified understanding. It may well be just as wrong as other views of Alzheimer’s disease.
We posit that Alzheimer’s disease (AD) is driven by amyloid-β (Aβ) generated in the amyloid-β protein precursor (AβPP) independent pathway, which is 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 by relegating its iAβ contribution to insignificance, and making its manipulation for therapeutic purposes, such as via 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.