Lecanemab, Aducanumab, and Gantenerumab — Binding Profiles to Different Forms of Amyloid-Beta Might Explain Efficacy and Side Effects in Clinical Trials for Alzheimer's Disease

Neurotherapeutics, Journal Year: 2022, Volume and Issue: 20(1), P. 195 - 206

Published: Oct. 17, 2022

Immunotherapy against amyloid-beta (Aβ) is a promising option for the treatment of Alzheimer's disease (AD). Aβ exists as various species, including monomers, oligomers, protofibrils, and insoluble fibrils in plaques. Oligomers protofibrils have been shown to be toxic, removal these aggregates might represent an effective AD. We characterized binding properties lecanemab, aducanumab, gantenerumab different species with inhibition ELISA, immunodepletion, surface plasmon resonance. All three antibodies bound monomers low affinity. However, lecanemab aducanumab had very weak somewhat stronger binding. Lecanemab was distinctive it tenfold compared fibrils. Aducanumab preferred over protofibrils. Our results show profiles that may explain clinical observed regarding both efficacy side effects.

Language: Английский

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The China Alzheimer Report 2022

General Psychiatry, Journal Year: 2022, Volume and Issue: 35(1), P. e100751 - e100751

Published: Feb. 1, 2022

China's population has rapidly aged over the recent decades of social and economic development as neurodegenerative disorders have proliferated, especially Alzheimer's disease (AD) related dementias (ADRD). AD's incidence rate, morbidity, mortality steadily increased to make it presently fifth leading cause death among urban rural residents in China magnify resulting financial burdens on individuals, families society. The 'Healthy Action' plan 2019-2030 promotes transition from treatment health maintenance for this expanding with ADRD. This report describes epidemiological trends, evaluates burden disease, outlines current clinical diagnosis status delineates existing available public resources. More specifically, examines impact ADRD, including prevalence, mortality, costs, usage care, overall effect caregivers In addition, special presents technical guidance supports prevention AD, provides expertise guide relevant governmental healthcare policy suggests an information platform international exchange cooperation.

Language: Английский

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Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer’s disease: a systematic review

Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 72, P. 101496 - 101496

Published: Oct. 22, 2021

Alzheimer's disease (AD) is the most prevalent neurodegenerative in ageing, affecting around 46 million people worldwide but few treatments are currently available. The etiology of AD still puzzling, and new drugs development clinical trials have high failure rates. Urgent outline an integral (multi-target) effective treatment needed. Accumulation amyloid-β (Aβ) peptides considered one fundamental neuropathological pillars disease, its dyshomeostasis has shown a crucial role onset. Therefore, many amyloid-targeted therapies been investigated. Here, we will systematically review recent (from 2014) investigational, follow-up studies focused on anti-amyloid strategies to summarize analyze their current potential. Combination anti-Aβ with developing early detection biomarkers other therapeutic agents acting functional changes be highlighted this review. Near-term approval seems likely for several against Aβ, FDA monoclonal oligomers antibody –aducanumab– raising hopes controversies. We conclude that, oligomer-epitope specific Aβ implementation multiple improved risk prediction methods allowing detection, together factors such as hyperexcitability AD, could key slowing global pandemic.

Language: Английский

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Blood biomarkers for Alzheimer’s disease in clinical practice and trials

Nature Aging, Journal Year: 2023, Volume and Issue: 3(5), P. 506 - 519

Published: May 18, 2023

Language: Английский

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Challenges and hopes for Alzheimer’s disease

Drug Discovery Today, Journal Year: 2022, Volume and Issue: 27(4), P. 1027 - 1043

Published: Feb. 1, 2022

Language: Английский

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

Frontiers in Aging Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: April 12, 2022

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

Language: Английский

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Approval of Aducanumab for Alzheimer Disease—The FDA’s Perspective

JAMA Internal Medicine, Journal Year: 2021, Volume and Issue: 181(10), P. 1276 - 1276

Published: July 13, 2021

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Language: Английский

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Aducanumab produced a clinically meaningful benefit in association with amyloid lowering

Alzheimer s Research & Therapy, Journal Year: 2021, Volume and Issue: 13(1)

Published: May 10, 2021

Language: Английский

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Amyloid Beta in Aging and Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(21), P. 12924 - 12924

Published: Oct. 26, 2022

Alzheimer’s disease (AD), is a progressive neurodegenerative that affects behavior, thinking, learning, and memory in elderly individuals. AD occurs two forms, early onset familial late-onset sporadic; genetic mutations PS1, PS2, APP genes cause AD, combination of lifestyle, environment factors causes the sporadic form disease. However, accelerated progression noticed patients with AD. Disease-causing pathological changes are synaptic damage, mitochondrial structural functional changes, addition to increased production accumulation phosphorylated tau (p-tau), amyloid beta (Aβ) affected brain regions patients. Aβ peptide derived from precursor protein (APP) by proteolytic cleavage gamma secretases. glycoprotein plays significant role maintaining neuronal homeostasis like signaling, development, intracellular transport. reported have both protective toxic effects neurons. The purpose our article summarize recent developments its association synapses, mitochondria, microglia, astrocytes, interaction p-tau. Our also covers therapeutic strategies reduce toxicities discusses reasons for failures therapeutics.

Language: Английский

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Lecanemab in patients with early Alzheimer’s disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study

Alzheimer s Research & Therapy, Journal Year: 2022, Volume and Issue: 14(1)

Published: Dec. 21, 2022

Abstract Background Lecanemab, a humanized IgG1 monoclonal antibody that targets soluble aggregated Aβ species (protofibrils), has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in early AD. The objective this analysis is to report results from study 201 blinded period (core), the open-label extension (OLE), gap (between core OLE) supporting effectiveness lecanemab. Methods lecanemab was double-blind, randomized, placebo-controlled 856 patients randomized one five dose regimens or placebo. An OLE initiated allow receive 10mg/kg biweekly for up 24 months, with an intervening off-treatment (gap period) ranging 9 59 months (mean months). Results At 12 18 treatment core, 10 mg/kg dose-dependent reductions measured PET corresponding changes plasma biomarkers cognitive decline. rates progression during were similar placebo subjects, differences maintained after discontinued dosing over average period. During gap, Aβ42/40 ratio p-tau181 levels began return towards pre-randomization more quickly than PET. baseline, vs at across 3 assessments. In OLE, produced SUVr, improvements ratio, p-tau181. Conclusions Lecanemab resulted significant plaques Data indicate rapid pronounced correlates benefit potential disease-modifying effects, as well use monitor effects. Trial registration ClinicalTrials.gov NCT01767311 .

Language: Английский

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