{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T22:32:36Z","timestamp":1793053956740,"version":"4.5.0"},"reference-count":185,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T00:00:00Z","timestamp":1690761600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["NIH R21 GM056179"],"award-info":[{"award-number":["NIH R21 GM056179"]}]},{"name":"National Institutes of Health","award":["NIH RO1 AR036819"],"award-info":[{"award-number":["NIH RO1 AR036819"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>With the long-standing amyloid cascade hypothesis (ACH) largely discredited, there is an acute need for a new all-encompassing interpretation of Alzheimer\u2019s disease (AD). Whereas such a recently proposed theory of AD is designated ACH2.0, its commonality with the ACH is limited to the recognition of the centrality of amyloid-\u03b2 (A\u03b2) in the disease, necessitated by the observation that all AD-causing mutations affect, in one way or another, A\u03b2. Yet, even this narrow commonality is superficial since AD-causing A\u03b2 of the ACH differs distinctly from that specified in the ACH2.0: Whereas in the former, the disease is caused by secreted extracellular A\u03b2, in the latter, it is triggered by A\u03b2-protein-precursor (A\u03b2PP)-derived intraneuronal A\u03b2 (iA\u03b2) and driven by iA\u03b2 generated independently of A\u03b2PP. The ACH2.0 envisions AD as a two-stage disorder. The first, asymptomatic stage is a decades-long accumulation of A\u03b2PP-derived iA\u03b2, which occurs via internalization of secreted A\u03b2 and through intracellular retention of a fraction of A\u03b2 produced by A\u03b2PP proteolysis. When A\u03b2PP-derived iA\u03b2 reaches critical levels, it activates a self-perpetuating A\u03b2PP-independent production of iA\u03b2 that drives the second, devastating AD stage, a cascade that includes tau pathology and culminates in neuronal loss. The present study analyzes the dynamics of iA\u03b2 accumulation in health and disease and concludes that it is the prime factor driving both AD and aging-associated cognitive decline (AACD). It discusses mechanisms potentially involved in A\u03b2PP-independent generation of iA\u03b2, provides mechanistic interpretations for all principal aspects of AD and AACD including the protective effect of the Icelandic A\u03b2PP mutation, the early onset of FAD and the sequential manifestation of AD pathology in defined regions of the affected brain, and explains why current mouse AD models are neither adequate nor suitable. It posits that while drugs affecting the accumulation of A\u03b2PP-derived iA\u03b2 can be effective only protectively for AD, the targeted degradation of iA\u03b2 is the best therapeutic strategy for both prevention and effective treatment of AD and AACD. It also proposes potential iA\u03b2-degrading drugs.<\/jats:p>","DOI":"10.3390\/ijms241512246","type":"journal-article","created":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T09:22:38Z","timestamp":1690795358000},"page":"12246","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["The Amyloid Cascade Hypothesis 2.0 for Alzheimer\u2019s Disease and Aging-Associated Cognitive Decline: From Molecular Basis to Effective Therapy"],"prefix":"10.3390","volume":"24","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":[[2023,7,31]]},"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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