{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:53:52Z","timestamp":1789988032914,"version":"4.0.1"},"reference-count":69,"publisher":"SAGE Publications","issue":"s1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2024,10,18]]},"abstract":"<jats:p>The amyloid hypothesis posits that the amyloid-\u03b2 aggregates in the brain initiate a cascade of events that eventually lead to neuron loss and Alzheimer\u2019s disease. Recent clinical trials of passive immunotherapy with anti-amyloid-\u03b2 antibodies support this hypothesis, because clearing plaques led to better cognitive outcomes. Orally available small molecule BACE1 inhibitors are another approach to slowing the buildup of plaques and thereby cognitive worsening by preventing the cleavage of amyloid-\u03b2 protein precursor (A\u03b2PP) into amyloid-\u03b2 peptide, the major component of plaques. This approach is particularly attractive because of their ease of use, low cost, and advanced clinical stage. However, although effective in preventing amyloid-\u03b2 production in late-stage clinical trials, BACE inhibitors have been associated with early, non-progressive, likely reversible, cognitive decline. The clinical trials tested high levels of BACE inhibition, greater than 50%, whereas genetics suggest that even a 30% inhibition may be sufficient to protect from Alzheimer\u2019s disease. Aside from A\u03b2PP, BACE1 cleaves many other substrates in the brain that may be contributing to the cognitive worsening. It is important to know what the cause of cognitive worsening is, and if a lower level of inhibition would sufficiently slow the progress of pathology while preventing these unwanted side effects. Should these side effects be mitigated, BACE inhibitors could rapidly move forward in clinical trials either as a primary prevention strategy in individuals that are at risk or biomarker positive, or as a maintenance therapy following amyloid clearance with an anti-amyloid antibody.<\/jats:p>","DOI":"10.3233\/jad-231258","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T10:51:55Z","timestamp":1729248715000},"page":"S41-S52","source":"Crossref","is-referenced-by-count":22,"title":["BACE Inhibitor Clinical Trials for Alzheimer\u2019s Disease"],"prefix":"10.1177","volume":"101","author":[{"given":"Elyse A.","family":"Watkins","sequence":"first","affiliation":[{"name":"Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Vassar","sequence":"additional","affiliation":[{"name":"Davee Department of Neurology, Feinberg School 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