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Cited by 568Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Anti-Amyloid-β Monoclonal Antibodies for Alzheimer’s Disease: Pitfalls and Promise

Open access
van Dyck, Christopher H.·2018·Biological Psychiatry
DOI 10.1016/j.biopsych.2017.08.010PMC PMC5767539
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Abstract

The majority of putative disease-modifying treatments in development for Alzheimer's disease are directed against the amyloid-β (Aβ) peptide. Among the anti-Aβ therapeutic approaches, the most extensively developed is immunotherapy-specifically, passive immunization through administration of exogenous monoclonal antibodies (mAbs). Although testing of mAbs has been fraught with failure and confusing results, the experience gained from these trials has provided important clues for better treatments. This review summarizes the experience to date with anti-Aβ mAbs to enter clinical trials for Alzheimer's disease and examines the evidence for clinical efficacy and the major problems with safety-i.e., amyloid-related imaging abnormalities. As mAbs differ considerably with regard to their epitopes and the conformations of Aβ that they recognize (monomers, oligomers, protofibrils, fibrils), the consequences of targeting different species are also considered. An often-cited explanation for the failure of anti-Aβ mAb trials is that they are set too late in the disease process. New trials are indeed evaluating treatments at prodromal and preclinical stages. We should expect to see additional studies of presymptomatic Alzheimer's disease to join the ongoing prevention trials, for which mAbs continue to serve as the mainstay.

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  • Based on phase 3 clinical trials, aducanumab can effectively lower amyloid PET ligand signals to the levels of controls in many individuals with early AD, but controversial data on possible cognitive and functional improvement have arisen.

    “Based on the results of phase 3 clinical trials, aducanumab can effectively lower amyloid PET ligand signals to the levels of controls in many individuals with early AD but controversial data on possible cognitive and functional improvement in AD patients treated with Aducanumab have arisen [40].”

    From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [40]

    The ADUCANUMAB section reports reduced brain amyloid on PET and exploratory slowing of clinical decline in people with prodromal or mild AD. But these findings came from a phase 1b study that was not powered for efficacy; the paper says the phase 3 trials were still enrolling. It does not establish that PET signals reached control levels in many participants or report phase 3 cognitive and functional results. Page numbers are unavailable in our copy. (LLM, conf=0.90)

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  • Anti-Aβ therapies should start decades before the onset of clinical symptoms to have significant influences on cognitive decline.

    “it is suggested that anti-Aβ therapies should start decades before the onset of clinical symptoms to have significant influences on cognitive decline [67–69].”

    From PCSK9 acts as a key regulator of Aβ clearance across the blood–brain barrier (2022) · cites this paper as [68]

    The “Importance of Stage of Disease” section says earlier anti-Aβ intervention is advantageous and later treatment may prove ineffective. It does not specify that treatment must begin decades before symptoms or establish that this timing is necessary to significantly affect cognitive decline; it explicitly says whether early intervention is necessary for any benefit is unclear. No page number is available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The majority of these monoclonal antibody drugs have severe side effects like ARIA, associated with vasogenic edema (ARIA-E) or indicating micro haemorrhage and hemosiderosis (ARIA-H).

    “But majority of these drugs have severe side effects like ARIA (Amyloid related imaging abnormalities), which are associated with vasogenic edema (ARIA-E) or indicate micro haemorrhage and hemosiderosis (ARIA-H) [120].”

    From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [120]

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Research works printed but not linked: 1

  1. [38]38. Cummings JL Cohen S van Dyck CH Brody M Curtis C Scheltens P (in press) Double-blind, placebo-controlled, randomized Phase II study of the anti-amyloid-beta antibody crenezumab (MABT5102A) in mild-to-moderate Alzheimer’s Disease (ABBY) Neurology

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Authors
van Dyck, C. H.
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2018-02
Volume
83
Issue
4
Pages
311-319
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2017.08.010
PMC
PMC5767539
OpenAlex
W2749751342
Cited by
568
References
69
Citations by year
2026: 31 · 2025: 58 · 2024: 55 · 2023: 73 · 2022: 101 · 2021: 69 · 2020: 80 · 2019: 65 · 2018: 36
FWCI
6.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
Funders
  • Yale University
  • National Institutes of Health (UH2TR000967, UL1TR000142, UL1TR001863)
  • National Institute on Aging (R01AG030457, R01AG052560, P50AG047270)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, amyloid-beta, anti-amyloid monoclonal antibodies, passive immunotherapy, amyloid-related imaging abnormalities, amyloid-beta oligomers, amyloid-beta protofibrils, amyloid-beta fibrils, disease-modifying therapy, clinical trial safety, prodromal Alzheimer's disease, preclinical Alzheimer's disease, prevention trials, treatment timing
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Antibodies, Monoclonal, Humans, Immunotherapy, Middle Aged, Amyloid beta-Peptides

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