ACH2.0/E, the Consolidated Theory of Conventional and Unconventional Alzheimer’s Disease: Origins, Progression, and Therapeutic Strategies
Authors: Volloch Vladimir , Rits-Volloch Sophia 
Published: May 2024

The centrality of amyloid-beta (Aβ) is an indisputable tenet of Alzheimer’s disease (AD). It was initially indicated by the detection (1991) of a mutation within Aβ protein precursor (AβPP) segregating with the disease, which served as a basis for the long-standing Amyloid Cascade Hypothesis (ACH) theory of AD. In the intervening three decades, this notion was affirmed and substantiated by the discovery of numerous AD-causing and AD-protective mutations with all, without an exception, affecting the structure, production, and intraneuronal degradation of Aβ. The ACH postulated that the disease is caused and driven by extracellular Aβ. When it became clear that this is not the case, and the ACH was largely discredited, a new theory of AD, dubbed ACH2.0 to re-emphasize the centrality of Aβ, was formulated. In the ACH2.0, AD is caused by physiologically accumulated intraneuronal Aβ (iAβ) derived from AβPP. Upon reaching the critical threshold, it triggers activation of the autonomous AβPP-independent iAβ generation pathway; its output is retained intraneuronally and drives the AD pathology. The bridge between iAβ derived from AβPP and that generated independently of AβPP is the neuronal integrated stress response (ISR) elicited by the former. The ISR severely suppresses cellular protein synthesis; concurrently, it activates the production of a small subset of proteins, which apparently includes components necessary for operation of the AβPP-independent iAβ generation pathway that are absent under regular circumstances. The above sequence of events defines “conventional” AD, which is both caused and driven by differentially derived iAβ. Since the ISR can be elicited by a multitude of stressors, the logic of the ACH2.0 mandates that another class of AD, referred to as “unconventional”, has to occur. Unconventional AD is defined as a disease where a stressor distinct from AβPP-derived iAβ elicits the neuronal ISR. Thus, the essence of both, conventional and unconventional, forms of AD is one and the same, namely autonomous, self-sustainable, AβPP-independent production of iAβ. What distinguishes them is the manner of activation of this pathway, i.e., the mode of causation of the disease. In unconventional AD, processes occurring at locations as distant from and seemingly as unrelated to the brain as, say, the knee can potentially trigger the disease. The present study asserts that these processes include traumatic brain injury (TBI), chronic traumatic encephalopathy, viral and bacterial infections, and a wide array of inflammatory conditions. It considers the pathways which are common to all these occurrences and culminate in the elicitation of the neuronal ISR, analyzes the dynamics of conventional versus unconventional AD, shows how the former can morph into the latter, explains how a single TBI can hasten the occurrence of AD and why it takes multiple TBIs to trigger the disease, and proposes the appropriate therapeutic strategies. It posits that yet another class of unconventional AD may occur where the autonomous AβPP-independent iAβ production pathway is initiated by an ISR-unrelated activator, and consolidates the above notions in a theory of AD, designated ACH2.0/E (for expanded ACH2.0), which incorporates the ACH2.0 as its special case and retains the centrality of iAβ produced independently of AβPP as the driving agent of the disease.