{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T18:40:54Z","timestamp":1770748854263,"version":"3.50.0"},"reference-count":231,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T00:00:00Z","timestamp":1717027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R21 GM056179"],"award-info":[{"award-number":["R21 GM056179"]}]},{"name":"NIH","award":["RO1 AR036819"],"award-info":[{"award-number":["RO1 AR036819"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The centrality of amyloid-beta (A\u03b2) is an indisputable tenet of Alzheimer\u2019s disease (AD). It was initially indicated by the detection (1991) of a mutation within A\u03b2 protein precursor (A\u03b2PP) 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 A\u03b2. The ACH postulated that the disease is caused and driven by extracellular A\u03b2. 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 A\u03b2, was formulated. In the ACH2.0, AD is caused by physiologically accumulated intraneuronal A\u03b2 (iA\u03b2) derived from A\u03b2PP. Upon reaching the critical threshold, it triggers activation of the autonomous A\u03b2PP-independent iA\u03b2 generation pathway; its output is retained intraneuronally and drives the AD pathology. The bridge between iA\u03b2 derived from A\u03b2PP and that generated independently of A\u03b2PP 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 A\u03b2PP-independent iA\u03b2 generation pathway that are absent under regular circumstances. The above sequence of events defines \u201cconventional\u201d AD, which is both caused and driven by differentially derived iA\u03b2. 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 \u201cunconventional\u201d, has to occur. Unconventional AD is defined as a disease where a stressor distinct from A\u03b2PP-derived iA\u03b2 elicits the neuronal ISR. Thus, the essence of both, conventional and unconventional, forms of AD is one and the same, namely autonomous, self-sustainable, A\u03b2PP-independent production of iA\u03b2. 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 A\u03b2PP-independent iA\u03b2 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 iA\u03b2 produced independently of A\u03b2PP as the driving agent of the disease.<\/jats:p>","DOI":"10.3390\/ijms25116036","type":"journal-article","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T03:46:49Z","timestamp":1717127209000},"page":"6036","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["ACH2.0\/E, the Consolidated Theory of Conventional and Unconventional Alzheimer\u2019s Disease: Origins, Progression, and Therapeutic Strategies"],"prefix":"10.3390","volume":"25","author":[{"given":"Vladimir","family":"Volloch","sequence":"first","affiliation":[{"name":"Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophia","family":"Rits-Volloch","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"369","DOI":"10.3233\/ADR-220031","article-title":"The Amyloid Cascade Hypothesis 2.0: On the possibility of once-in-a-lifetime-only treatment for prevention of Alzheimer\u2019s disease and for its potential cure at symptomatic stages","volume":"6","author":"Volloch","year":"2022","journal-title":"J. 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