{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T20:17:38Z","timestamp":1792700258227,"version":"4.5.0"},"reference-count":70,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T00:00:00Z","timestamp":1623628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A large body of clinical and nonclinical evidence supports the role of neurotoxic soluble beta amyloid (amyloid, A\u03b2) oligomers as upstream pathogenic drivers of Alzheimer\u2019s disease (AD). Recent late-stage trials in AD that have evaluated agents targeting distinct species of A\u03b2 provide compelling evidence that inhibition of A\u03b2 oligomer toxicity represents an effective approach to slow or stop disease progression: (1) only agents that target soluble A\u03b2 oligomers show clinical efficacy in AD patients; (2) clearance of amyloid plaque does not correlate with clinical improvements; (3) agents that predominantly target amyloid monomers or plaque failed to show clinical effects; and (4) in positive trials, efficacy is greater in carriers of the \u03b54 allele of apolipoprotein E (APOE4), who are known to have higher brain concentrations of A\u03b2 oligomers. These trials also show that inhibiting A\u03b2 neurotoxicity leads to a reduction in tau pathology, suggesting a pathogenic sequence of events where amyloid toxicity drives an increase in tau formation and deposition. The late-stage agents with positive clinical or biomarker data include four antibodies that engage A\u03b2 oligomers (aducanumab, lecanemab, gantenerumab, and donanemab) and ALZ-801, an oral agent that fully blocks the formation of A\u03b2 oligomers at the clinical dose.<\/jats:p>","DOI":"10.3390\/ijms22126355","type":"journal-article","created":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T10:30:25Z","timestamp":1623666625000},"page":"6355","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":241,"title":["Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer\u2019s Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3910-091X","authenticated-orcid":false,"given":"Martin","family":"Tolar","sequence":"first","affiliation":[{"name":"Alzheon, Inc., Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Hey","sequence":"additional","affiliation":[{"name":"Alzheon, Inc., Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aidan","family":"Power","sequence":"additional","affiliation":[{"name":"Alzheon, Inc., Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Abushakra","sequence":"additional","affiliation":[{"name":"Alzheon, Inc., Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S21","DOI":"10.1016\/S0197-4580(97)00065-1","article-title":"Neuropathological diagnosis of Alzheimer\u2019s disease: A perspective from longitudinal clinicopathological studies","volume":"18","author":"Dickson","year":"1997","journal-title":"Neurobiol. 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