{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T22:04:31Z","timestamp":1789164271121,"version":"build-2803163510"},"reference-count":261,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH USA","award":["NIH R21 GM056179"],"award-info":[{"award-number":["NIH R21 GM056179"]}]},{"name":"NIH USA","award":["NIH RO1 AR036819"],"award-info":[{"award-number":["NIH RO1 AR036819"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In the Amyloid Cascade Hypothesis (ACH2.0) paradigm, Alzheimer\u2019s disease (AD) is defined as a disorder triggered by a sustained neuronal integrated stress response (ISR) and driven by the C99 fragment of amyloid-beta protein precursor (A\u03b2PP) generated in the autonomous A\u03b2PP-independent pathway. This implies that AD can be initiated by any stressor capable of activating one or more of the four eIF2\u03b1 kinases and accumulated intraneuronally to sufficient levels. In most instances of AD, such a stressor is intraneuronal A\u03b2 (iA\u03b2) accumulated to a PKR- and\/or HRI-activating concentration and designated, in terms of the ACH2.0, as a \u201cconventional stressor\u201d. The ensuing disease is referred to, accordingly, as \u201cconventional AD\u201d. Any stressor other than iA\u03b2, which is capable of activating one or more eIF2\u03b1 kinases in neuronal cells, is designated as an \u201cunconventional stressor\u201d. At a sufficient concentration, it triggers elicitation of the neuronal ISR and initiates the disease, referred to in terms of the ACH2.0 as \u201cunconventional AD\u201d, at levels of iA\u03b2 below those required for activation of PKR and\/or HRI. In both forms of AD, the neuronal ISR activates production of components essential for, and, consequently, enables operation of, the RNA-dependent mRNA amplification pathway. Human A\u03b2PP mRNA is eligible for this process, and its asymmetric amplification yields 5\u2032-truncated mRNA molecules that are translated into C99 at rates that are orders of magnitude greater than those seen in A\u03b2PP proteolysis. The resulting C99 drives AD pathology; it also propagates the ISR state and perpetuates both its own production and the progression of the disease. Thus, the neuronal ISR-enabled amplification of A\u03b2PP mRNA constitutes the active core of AD. It follows that the essence of any effective therapy for AD, in both conventional and unconventional forms, is to either prevent activation or suppress the operation of the A\u03b2PP mRNA amplification process. The present perspective considers therapeutic options capable of accomplishing these objectives. They include inhibition of the neuronal ISR, targeted degradation of iA\u03b2 and C99, anti-antisense oligonucleotides (AASO) for A\u03b2PP RNA, and the restructuring of the 5\u2032 terminus of A\u03b2PP mRNA. Collectively, these therapeutic approaches constitute the state of the art in the ACH2.0 paradigm; if successful, they would render both AD and aging-associated cognitive decline (AACD) obsolete. This study also describes transgenic animal and human neuronal cell-based models of both conventional and unconventional forms of AD that are suitable for testing the proposed therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms27031486","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T09:00:58Z","timestamp":1770109258000},"page":"1486","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Therapeutic Options for Alzheimer\u2019s Disease and Aging-Associated Cognitive Decline: State of the Art in the ACH2.0 Paradigm"],"prefix":"10.3390","volume":"27","author":[{"given":"Vladimir","family":"Volloch","sequence":"first","affiliation":[{"name":"Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,2]]},"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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