Searching for just a few words should be enough to get started. If you need to make more complex queries, use the tips below to guide you.
Issue title: Therapeutic Trials in Alzheimer’s Disease: Where Are We Now?
Guest editors: Paula I. Moreira, Jesus Avila, Daniela Galimberti, Miguel A. Pappolla, Germán Plascencia-Villa, Aaron A. Sorensen, Xiongwei Zhu and George Perry
Article type: Review Article
Authors: Watkins, Elyse A.a | Vassar, Roberta; b; *
Affiliations: [a] Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA | [b] Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
Correspondence: [*] Correspondence to: Robert Vassar, Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. E-mail: r-vassar@northwestern.edu.
Abstract: The amyloid hypothesis posits that the amyloid-β aggregates in the brain initiate a cascade of events that eventually lead to neuron loss and Alzheimer’s disease. Recent clinical trials of passive immunotherapy with anti-amyloid-β 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-β protein precursor (AβPP) into amyloid-β 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-β 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’s disease. Aside from AβPP, 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.
Keywords: Alzheimer’s disease, amyloid-β protein precursor, beta-secretase, clinical trial
DOI: 10.3233/JAD-231258
Journal: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S41-S52, 2024
IOS Press, Inc.
6751 Tepper Drive
Clifton, VA 20124
USA
Tel: +1 703 830 6300
Fax: +1 703 830 2300
sales@iospress.com
For editorial issues, like the status of your submitted paper or proposals, write to editorial@iospress.nl
IOS Press
Nieuwe Hemweg 6B
1013 BG Amsterdam
The Netherlands
Tel: +31 20 688 3355
Fax: +31 20 687 0091
info@iospress.nl
For editorial issues, permissions, book requests, submissions and proceedings, contact the Amsterdam office info@iospress.nl
Inspirees International (China Office)
Ciyunsi Beili 207(CapitaLand), Bld 1, 7-901
100025, Beijing
China
Free service line: 400 661 8717
Fax: +86 10 8446 7947
china@iospress.cn
For editorial issues, like the status of your submitted paper or proposals, write to editorial@iospress.nl
如果您在出版方面需要帮助或有任何建, 件至: editorial@iospress.nl