{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T18:39:21Z","timestamp":1770748761133,"version":"3.50.0"},"reference-count":150,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T00:00:00Z","timestamp":1702857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["RO1 AR036819"],"award-info":[{"award-number":["RO1 AR036819"]}]},{"name":"NIH","award":["R21 GM056179"],"award-info":[{"award-number":["R21 GM056179"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Although the long-standing Amyloid Cascade Hypothesis (ACH) has been largely discredited, its main attribute, the centrality of amyloid-beta (A\u03b2) in Alzheimer\u2019s disease (AD), remains the cornerstone of any potential interpretation of the disease: All known AD-causing mutations, without a single exception, affect, in one way or another, A\u03b2. The ACH2.0, a recently introduced theory of AD, preserves this attribute but otherwise differs fundamentally from the ACH. It posits that AD is a two-stage disorder where both stages are driven by intraneuronal (rather than extracellular) A\u03b2 (iA\u03b2) albeit of two distinctly different origins. The first asymptomatic stage is the decades-long accumulation of A\u03b2 protein precursor (A\u03b2PP)-derived iA\u03b2 to the critical threshold. This triggers the activation of the self-sustaining A\u03b2PP-independent\u00a0iA\u03b2 production pathway and the commencement of the second, symptomatic AD stage. Importantly, A\u03b2 produced independently of A\u03b2PP is retained intraneuronally. It drives the AD pathology and perpetuates the operation of the pathway; continuous cycles of the iA\u03b2-stimulated propagation of its own A\u03b2PP-independent production constitute an engine that drives AD, the AD Engine. It appears that the dynamics of A\u03b2PP-derived iA\u03b2 accumulation is the determining factor that either drives Aging-Associated Cognitive Decline (AACD) and triggers AD or confers the resistance to both. Within the ACH2.0 framework, the ACH-based drugs, designed to lower levels of extracellular A\u03b2, could be applicable in the prevention of AD and treatment of AACD because they reduce the rate of accumulation of A\u03b2PP-derived iA\u03b2. The present study analyzes their utility and concludes that it is severely limited. Indeed, their short-term employment is ineffective, their long-term engagement is highly problematic, their implementation at the symptomatic stages of AD is futile, and their evaluation in conventional clinical trials for the prevention of AD is impractical at best, impossible at worst, and misleading in between. In contrast, the ACH2.0-guided Next Generation Therapeutic Strategy for the treatment and prevention of both AD and AACD, namely the depletion of iA\u03b2 via its transient, short-duration, targeted degradation by the novel ACH2.0-based drugs, has none of the shortcomings of the ACH-based drugs. It is potentially highly effective, easily evaluable in clinical trials, and opens up the possibility of once-in-a-lifetime-only therapeutic intervention for prevention and treatment of both conditions. It also identifies two plausible ACH2.0-based drugs: activators of physiologically occurring intra-iA\u03b2-cleaving capabilities of BACE1 and\/or BACE2.<\/jats:p>","DOI":"10.3390\/ijms242417586","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T03:59:24Z","timestamp":1702871964000},"page":"17586","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Next Generation Therapeutic Strategy for Treatment and Prevention of Alzheimer\u2019s Disease and Aging-Associated Cognitive Decline: Transient, Once-in-a-Lifetime-Only Depletion of Intraneuronal A\u03b2 (iA\u03b2) by Its Targeted Degradation via Augmentation of Intra-iA\u03b2-Cleaving Activities of BACE1 and\/or BACE2"],"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":[{"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":[[2023,12,18]]},"reference":[{"key":"ref_1","first-page":"369","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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