{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T17:45:45Z","timestamp":1773078345520,"version":"3.50.1"},"reference-count":47,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,6,2]],"date-time":"2018-06-02T00:00:00Z","timestamp":1527897600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>The present review analyzes the results of recent clinical trials of \u03b2 secretase inhibition in sporadic Alzheimer\u2019s disease (SAD), considers the striking dichotomy between successes in tests of \u03b2-site Amyloid Precursor Protein-Cleaving Enzyme (BACE) inhibitors in healthy subjects and familial Alzheimer\u2019s disease (FAD) models versus persistent failures of clinical trials and interprets it as a confirmation of key predictions for a mechanism of amyloid precursor protein (APP)-independent, \u03b2 secretase inhibition-resistant production of \u03b2 amyloid in SAD, previously proposed by us. In light of this concept, FAD and SAD should be regarded as distinctly different diseases as far as \u03b2-amyloid generation mechanisms are concerned, and whereas \u03b2 secretase inhibition would be neither applicable nor effective in the treatment of SAD, the \u03b2-site APP-Cleaving Enzyme (BACE) inhibitor(s) deemed failed in SAD trials could be perfectly suitable for the treatment of FAD. Moreover, targeting the aspects of Alzheimer\u2019s disease (AD) other than cleavages of the APP by \u03b2 and \u03b1 secretases should have analogous impacts in both FAD and SAD.<\/jats:p>","DOI":"10.3390\/medsci6020045","type":"journal-article","created":{"date-parts":[[2018,6,4]],"date-time":"2018-06-04T08:52:03Z","timestamp":1528102323000},"page":"45","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Results of Beta Secretase-Inhibitor Clinical Trials Support Amyloid Precursor Protein-Independent Generation of Beta Amyloid in Sporadic Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"6","author":[{"given":"Vladimir","family":"Volloch","sequence":"first","affiliation":[{"name":"Deptartment of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophia","family":"Rits","sequence":"additional","affiliation":[{"name":"Howard Hughes Medical Institute at Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Deptartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,6,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1038\/nm1295-1291","article-title":"The Swedish mutation causes early-onset Alzheimer\u2019s disease by beta-secretase cleavage within the secretory pathway","volume":"1","author":"Haass","year":"1995","journal-title":"Nat. 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