Impact of Anti-amyloid-β Monoclonal Antibodies on the Pathology and Clinical Profile of Alzheimer’s Disease: A Focus on Aducanumab and Lecanemab

Abstract

Alzheimer’s disease (AD) is the most prevalent form of age-related dementia in the world, and its main pathological features consist of amyloid-β (Aβ) plaque deposits and neurofibrillary tangles formed by hyperphosphorylated tau protein. So far, only a few AD treatments approved have been applied in the clinic, but the effects of these drugs are limited only for partial symptomatic relief to patients with AD and are unable to alter AD progression. Later, all efforts for AD treatments with targeting the pathogenic factors were unsuccessful over the past decades, which suggested that the pathogenesis of AD is complex. Recently, disease-modifying therapies (DMTs) that can change the underlying pathophysiology of AD, with anti-Aβ monoclonal antibodies (mabs) (e.g., aducanumab, bapineuzumab, gantenerumab, solanezumab, and lecanemab) have been developed successively and conducted in clinical trials based on the theory that a systemic failure of cell-mediated Aβ clearance contributes to AD occurrence and progression. In the review, we summarized recent studies on the therapeutic effects and clinical trial results of these mabs in patients with AD. Specifically, we focused on the discussion of the impact of aducanumab and lecanemab on AD pathology and clinical profiles. The review provides a possible evidence for applying immunotherapy with anti-Aβ mabs in AD and analyzes lessons learned from these clinical trials in order to further study the therapeutic and adverse effects of these anti-Aβ mabs on AD.

New, Fully Implantable Device for Selective Clearance of CSF-Target Molecules: Proof of Concept in a Murine Model of Alzheimer’s Disease

“…However, a reduction of both plaques and intracellular Aβ has previously been reported to be associated with some cognitive impairments in murine models of AD [ 28 ]. Nevertheless, this is not the case in clinical trials with systemically administered anti-Aβ mAb which, while showing effective removal of plaques, no significant clinical benefit was found [ 13 , 14 ]. Indeed, plaque formation itself could be a defense mechanism [ 4 ], and densely deposited Aβ may not result as toxic as previously thought.…”

“…Indeed, plaque formation itself could be a defense mechanism [ 4 ], and densely deposited Aβ may not result as toxic as previously thought. Furthermore, the most toxic species of Aβ are oligomeric soluble forms [ 31 , 32 ], which is now perceived as an advantage of mAb specifically addressed against them [ 13 ]. Although in this study we have not detected changes in soluble Aβ in brain parenchyma or plasma, it is possible that longer apheresis times may have the capacity to modify the levels of these more toxic Aβ species.…”

“…Different approaches have been investigated to remove Aβ both biologically and mechanically, from decreasing production (i.e., BACE inhibitors) to increasing clearance in the periphery (immunotherapy, plasmapheresis, enzymatic degradation) [ 12 ]. Among them, immunotherapy with anti-Aβ monoclonal antibodies (mAb) is the most extensively explored in humans, showing the capacity to clear brain plaques and restore levels of soluble Aβ in the CNS [ 13 ]. However, none of these therapies have shown clinically relevant benefits to AD patients, and serious side effects have been reported, including amyloid-related imaging abnormalities (ARIA) after anti-Aβ mAb therapies [ 14 ].…”

Accelerated neuronal aging in vitro ∼melting watch ∼

“…Approaches for mechanistic elucidation of the onset and progression in various neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS) have led to the development of disease-modifying therapies to prevent neurodegeneration itself ( Kritsilis et al, 2018 ; Hou et al, 2019 ; Bobkova et al, 2020 ; Gendron et al, 2020 ). There are several potential candidates for disease-modifying therapies for ALS, AD, and PD, including AAV-mediated gene therapies and antibody-based approaches and cell transplantation ( Doi et al, 2020 ; Amado and Davidson, 2021 ; Tampi et al, 2021 ; Cummings et al, 2022 ; Rahimpour et al, 2022 ; Shi et al, 2022 ; Takahashi and Mashima, 2022 ). However, these approaches are yet under clinical trials or debates, and not thoroughly validated in human.…”

Symptomatic and Promising Disease-Modifying Treatments for Dementia Syndromes

“…For instance, phenolic compounds with antioxidant properties, including oleuropein and epigallocatechin gallate (EGCG) will be considered an effective intervention in dementia treatment (15). Ultimately, oligomers monoclonal antibodies with promising jpc.tums.ac.ir September 2022; 10(3) efficacy could bind to insoluble fibrils and soluble Ab protofibrils, thus, relieving the brain's Ab burden with a positive impact on cognition (16). Aducanumab is an Ab-targeting monoclonal antibody that is currently showing a significant dose-dependent reduction of Ab plaques' size.…”