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      Aducanumab Therapy to Treat Alzheimer's Disease: A Narrative Review

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          Abstract

          Background

          Aducanumab, a new monoclonal antibody that targets β-amyloid aggregates, has been granted conditional approval by the U.S. FDA for treatment of mild Alzheimer's disease (AD). The approval of this drug without a confirmed significant clinical impact has resulted in several debates.

          Objective

          In this narrative review, aducanumab approval-related controversy, the drug's pharmacokinetics and pharmacodynamic characteristics, evidence from the efficacy and safety trials of aducanumab, implications of the drug approval, and the future directions in the management of patients with AD are summarized.

          Methods

          Using relevant keywords, Google Scholar, Web of Science, and MEDLINE databases and manufacturer's website were searched.

          Results

          Infusion of aducanumab at a higher dose resulted in a modest slowing of cognitive decline among patients with mild cognitive impairment or early-onset AD dementia. The drug however can cause amyloid-related imaging abnormalities. Due to modest impact on cognition, the use of this drug by patients with AD will most likely be limited. The manufacturer is required to run an extended phase IIIb trial to verify the benefit of this drug. Access to therapy requires a careful selection of patients and periodic monitoring to ensure the optimal use of the drug.

          Conclusion

          Despite the limitations, aducanumab is the first disease-modifying therapy approved for the treatment of AD. Aducanumab addresses a part of the pathogenesis of AD; therefore, drugs that can act on multiple targets are needed. In addition, the search for preventive strategies, validated plasma-based assays, and newer drugs for AD, which are effective, safe, convenient, and affordable, is vital.

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          Most cited references65

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          Neuropathological stageing of Alzheimer-related changes

          Eighty-three brains obtained at autopsy from nondemented and demented individuals were examined for extracellular amyloid deposits and intraneuronal neurofibrillary changes. The distribution pattern and packing density of amyloid deposits turned out to be of limited significance for differentiation of neuropathological stages. Neurofibrillary changes occurred in the form of neuritic plaques, neurofibrillary tangles and neuropil threads. The distribution of neuritic plaques varied widely not only within architectonic units but also from one individual to another. Neurofibrillary tangles and neuropil threads, in contrast, exhibited a characteristic distribution pattern permitting the differentiation of six stages. The first two stages were characterized by an either mild or severe alteration of the transentorhinal layer Pre-alpha (transentorhinal stages I-II). The two forms of limbic stages (stages III-IV) were marked by a conspicuous affection of layer Pre-alpha in both transentorhinal region and proper entorhinal cortex. In addition, there was mild involvement of the first Ammon's horn sector. The hallmark of the two isocortical stages (stages V-VI) was the destruction of virtually all isocortical association areas. The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations.
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            The amyloid hypothesis of Alzheimer's disease at 25 years

            Abstract Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.
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              Alzheimer's disease: the amyloid cascade hypothesis

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                Author and article information

                Contributors
                Journal
                Int J Alzheimers Dis
                Int J Alzheimers Dis
                ijad
                International Journal of Alzheimer's Disease
                Hindawi
                2090-8024
                2090-0252
                2022
                9 March 2022
                : 2022
                : 9343514
                Affiliations
                1Clinical Pharmacy & Pharmacotherapeutics Department, Dubai Pharmacy College, Dubai, UAE
                2College of Medicine, Gulf Medical University, Ajman, UAE
                3College of Pharmacy, Gulf Medical University, Ajman, UAE
                4Department of Primary Care Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
                5Department of Pharmaceutical Sciences, College of Pharmacy, Al Ain University, Al Ain, Abu Dhabi, UAE
                6Department of Pharmacy Practice, College of Pharmacy, Gulf Medical University, Ajman, UAE
                Author notes

                Academic Editor: giulia abate

                Author information
                https://orcid.org/0000-0003-4990-4783
                https://orcid.org/0000-0002-4455-9872
                https://orcid.org/0000-0002-7861-5158
                https://orcid.org/0000-0003-3400-730X
                https://orcid.org/0000-0001-6314-2485
                https://orcid.org/0000-0002-2030-0962
                Article
                10.1155/2022/9343514
                8926483
                35308835
                9db822ec-5ec4-44cd-a4aa-aabd204f34b8
                Copyright © 2022 Semira Abdi Beshir et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 September 2021
                : 16 February 2022
                Categories
                Review Article

                Neurology
                Neurology

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