{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T03:03:20Z","timestamp":1786676600277,"version":"build-2736575974"},"reference-count":75,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Emerging evidence is challenging the long-standing notion that Alzheimer\u2019s disease (AD) is caused by increased \u03b3-secretase function and overproduction of 42-amino acid amyloid-beta (A\u03b242). CSF levels of soluble monomeric A\u03b242 in AD are reduced to about half of those in healthy individuals and drop even further at dementia onset in genetic forms (APP, PSEN1, PSEN2 mutations) and in Down syndrome.<\/jats:p>\n                  <jats:p>Findings supporting a revised AD pathophysiology include: (i) \u223c90% of pathogenic PSEN1 mutations reduce \u03b3-secretase activity and A\u03b242 production; (ii) lower \u03b3-secretase activity is correlated with lower soluble A\u03b242 levels, earlier onset of dementia, worse cognition, and faster progression; (iii) higher soluble A\u03b242 levels associate with preserved cognition and delayed dementia in amyloid-positive sporadic and familial AD; (iv) apparent cognitive benefits from anti-amyloid monoclonal antibodies involve increased soluble A\u03b242 levels; and (v) monomeric A\u03b242 supports memory and other functions akin to a neuropeptide.<\/jats:p>\n                  <jats:p>These findings suggest that restoring, not reducing, \u03b3-secretase activity and monomeric A\u03b242 levels above a compensation threshold could offer disease-modifying therapeutic benefits. Drugs that increase soluble A\u03b242, some already approved for other indications and linked to reduced dementia risk, may be repurposed to test whether they can slow disease progression in familial and sporadic AD.<\/jats:p>","DOI":"10.1093\/brain\/awaf294","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T11:53:15Z","timestamp":1754567595000},"page":"3856-3864","source":"Crossref","is-referenced-by-count":8,"title":["Restoring amyloid-\u03b242 and \u03b3-secretase function in Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3389-136X","authenticated-orcid":false,"given":"Alberto J","family":"Espay","sequence":"first","affiliation":[{"name":"James J. and Joan A. 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