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The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics

Abstract

Many drugs that target amyloid-β (Aβ) in Alzheimer disease (AD) have failed to demonstrate clinical efficacy. However, four anti-Aβ antibodies have been shown to mediate the removal of amyloid plaque from brains of patients with AD, and the FDA has recently granted accelerated approval to one of these, aducanumab, using reduction of amyloid plaque as a surrogate end point. The rationale for approval and the extent of the clinical benefit from these antibodies are under intense debate. With the aim of informing this debate, we review clinical trial data for drugs that target Aβ from the perspective of the temporal interplay between the two pathognomonic protein aggregates in AD — Aβ plaques and tau neurofibrillary tangles — and their relationship to cognitive impairment, highlighting differences in drug properties that could affect their clinical performance. On this basis, we propose that Aβ pathology drives tau pathology, that amyloid plaque would need to be reduced to a low level (~20 centiloids) to reveal significant clinical benefit and that there will be a lag between the removal of amyloid and the potential to observe a clinical benefit. We conclude that the speed of amyloid removal from the brain by a potential therapy will be important in demonstrating clinical benefit in the context of a clinical trial.

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Fig. 1: The amyloid hypothesis of Alzheimer disease.
Fig. 2: Aβ epitopes of monoclonal antibodies tested in clinical trials for Alzheimer disease.
Fig. 3: The relationship between amyloid removal and clinical response.
Fig. 4: Amyloid-β removal profiles for aducanumab, donanemab and lecanemab.

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Correspondence to Eric Karran.

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E.K. is in an employee and stockholder of AbbVie. AbbVie has an anti-Aβ monoclonal antibody entering phase I clinical studies. B.D.S. is or has been a consultant for Eli Lilly, Biogen, Janssen Pharmaceutica, Eisai, AbbVie and other companies. B.D.S is also a scientific founder of Augustine Therapeutics and a scientific founder and stockholder of Muna Therapeutics.

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Biogen plans regulatory filing for aducanumab in Alzheimer’s disease based on new analysis of larger dataset from phase 3 studies: https://investors.biogen.com/news-releases/news-release-details/biogen-plans-regulatory-filing-aducanumab-alzheimers-disease

Eisai and Biogen announce detailed results of phase II clinical study of BAN2401 in early Alzheimer’s disease at Alzheimer’s Association International Conference (AAIC) 2018: https://eisai.mediaroom.com/2018-07-25-Eisai-And-Biogen-Announce-Detailed-Results-Of-Phase-II-Clinical-Study-Of-BAN2401-In-Early-Alzheimers-Disease-At-Alzheimers-Association-International-Conference-AAIC-2018

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Karran, E., De Strooper, B. The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics. Nat Rev Drug Discov 21, 306–318 (2022). https://doi.org/10.1038/s41573-022-00391-w

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