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The studies were terminated early, and the reversibility of umibecestat's side effects was assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Cognitively unimpaired 60\u2010 to 75\u2010year\u2010old apolipoprotein E (\n                      <jats:italic>APOE<\/jats:italic>\n                      )\u00a0\u03b54 homozygotes and heterozygotes (the latter with elevated brain amyloid deposition) (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a01556) received umibecestat (50 or 15\u00a0mg daily) or placebo for 7 months on average and were followed for a median (interquartile range) of 4 (3 to 6) months after washout.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Compared to placebo, umibecestat\u2010treated participants had small, non\u2010progressive, but statistically significant decline in performance on certain cognitive batteries including Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and API Preclinical Composite Cognitive test, but not Clinical Dementia Rating\u2010Sum of Boxes. RBANS differences were no longer significant at the end of follow\u2010up.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>In people at genetic risk for AD, high\u2010dose beta\u2010site amyloid precursor protein cleaving enzyme (BACE) inhibition was associated with early mild cognitive worsening, which reversed shortly after washout, suggesting a symptomatic side effect not associated with neurodegeneration. Fully anonymized data, images, and samples are available upon request for further research on BACE inhibition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>This is the first trial with blinded assessment of reversibility of BACE inhibitor side effects.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Umibecestat was tested in cognitively unimpaired persons at genetic risk for AD.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Umibecestat led to early mild cognitive decline that reversed shortly after washout.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>This suggests a potentially manageable effect not associated with neurodegeneration.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Further research may determine the future of BACE inhibition in AD prevention.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.14237","type":"journal-article","created":{"date-parts":[[2024,9,25]],"date-time":"2024-09-25T11:41:53Z","timestamp":1727264513000},"page":"7745-7761","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Reversibility of cognitive worsening observed with BACE inhibitor umibecestat in the Alzheimer's Prevention Initiative (API) Generation Studies"],"prefix":"10.1002","volume":"20","author":[{"given":"Pierre N.","family":"Tariot","sequence":"first","affiliation":[{"name":"Banner Alzheimer's Institute  Phoenix Arizona USA"},{"name":"Department of Psychiatry University of Arizona College of Medicine  Phoenix Arizona USA"},{"name":"Arizona Alzheimer's Consortium  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Emmanuelle","family":"Riviere","sequence":"additional","affiliation":[{"name":"Clinical Development, Neuroscience Novartis Pharma AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Salloway","sequence":"additional","affiliation":[{"name":"Neurology and the Memory and Aging Program Butler Hospital  Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M.","family":"Burns","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Kansas Alzheimer's Disease Research Center  Mission Kansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f3n G.","family":"Snaedal","sequence":"additional","affiliation":[{"name":"Memory Clinic Landspitali University Hospital  Reykjavik Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth","family":"Borowsky","sequence":"additional","affiliation":[{"name":"Clinical development, Neuroscience Novartis Pharmaceuticals  East Hanover New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina Lopez","family":"Lopez","sequence":"additional","affiliation":[{"name":"Clinical Development, Neuroscience Novartis Pharma AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fonda","family":"Liu","sequence":"additional","affiliation":[{"name":"Clinical development, Neuroscience Novartis Pharmaceuticals  East Hanover New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Laure","family":"Rouzade\u2010Dominguez","sequence":"additional","affiliation":[{"name":"Clinical Development, Neuroscience Novartis Pharma AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pilar","family":"Cazorla","sequence":"additional","affiliation":[{"name":"Clinical development, Neuroscience Novartis Pharmaceuticals  East Hanover New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Catherine","family":"Mousseau","sequence":"additional","affiliation":[{"name":"Global Business Solutions, Neuroscience Novartis Ireland Ltd  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Arkuszewski","sequence":"additional","affiliation":[{"name":"Clinical Development, Neuroscience Novartis Pharma AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Ricart","sequence":"additional","affiliation":[{"name":"Clinical Development, Neuroscience Novartis Farmaceutica, S.A.  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