The case for low‐dose BACE inhibition

Background Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Positive trials of anti‐amyloid‐β immunotherapy have confirmed that amyloid contributes to cognitive deficits in patients. However, these therapies are cost...

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Bibliographic Details
Published in:Alzheimer's & dementia 2023-12, Vol.19 (S24), p.n/a
Main Authors: Watkins, Elyse, Vassar, Robert J.
Format: Article
Language:English
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Summary:Background Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Positive trials of anti‐amyloid‐β immunotherapy have confirmed that amyloid contributes to cognitive deficits in patients. However, these therapies are costly and require monthly or bi‐weekly infusions. Furthermore, in their current state, anti‐amyloid immunotherapy is approved for treatment of AD once symptoms have already appeared, which may be late in the cascade of neuronal damage. There is substantial need for an inexpensive and minimally invasive preventative therapy that could be taken during the pre‐symptomatic stage of AD, or in combination with amyloid immunotherapy to be taken after amyloid clearance to prevent the reemergence of plaques. Small‐molecule inhibitors of β‐site amyloid precursor protein (APP)‐cleaving enzyme 1 (BACE1) reduce the production of amyloid‐β peptide, are taken orally, and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment primarily in memory domains, and trials that have conducted follow‐up testing after study completion suggest that the cognitive impairment is reversible. In this talk, I discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors. Method N/A Result N/A Conclusion N/A
ISSN:1552-5260
1552-5279
DOI:10.1002/alz.082782