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The failures of several amyloid\u2010targeted programs have led many to dismiss the amyloid beta (A\u03b2) hypothesis of AD. An antiamyloid antibody aducanumab recently showed modest but significant efficacy in a phase 3 trial, providing important validation of amyloid as a therapeutic target. However, the inconsistent results observed with aducanumab may be explained by the limited brain penetration and lack of selectivity for the soluble A\u03b2 oligomers, which are implicated as upstream drivers of neurodegeneration by multiple studies. Development of agents that can effectively inhibit A\u03b2 oligomer formation or block their toxicity is therefore warranted. An ideal drug would cross the blood\u2010brain barrier efficiently and achieve sustained brain levels that can continuously prevent oligomer formation or inhibit their toxicity. A late\u2010stage candidate with these attributes is ALZ\u2010801, an oral drug with a favorable safety profile and high brain penetration that can robustly inhibit A\u03b2 oligomer formation. An upcoming phase 3 trial with ALZ\u2010801 in APOE4\/4 homozygous patients with early AD will effectively test this amyloid oligomer hypothesis.<\/jats:p>","DOI":"10.1016\/j.jalz.2019.09.075","type":"journal-article","created":{"date-parts":[[2019,11,6]],"date-time":"2019-11-06T03:04:46Z","timestamp":1573009486000},"page":"1553-1560","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":253,"title":["The path forward in Alzheimer's disease therapeutics: Reevaluating the amyloid cascade hypothesis"],"prefix":"10.1002","volume":"16","author":[{"given":"Martin","family":"Tolar","sequence":"first","affiliation":[{"name":"Alzheon, Inc  Framingham MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Abushakra","sequence":"additional","affiliation":[{"name":"Alzheon, Inc  Framingham MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwan","family":"Sabbagh","sequence":"additional","affiliation":[{"name":"Cleveland Clinic Lou Ruvo Center for Brain Health  Las Vegas NV USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,1,3]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"Center for Drug Evaluation and Research. 2018 New Drug Therapy Approvals. 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