Role of Aducanumab in the Treatment of Alzheimer’s Disease: Challenges and Opportunities DOI Creative Commons
Miguel Vaz, Vítor Silva, Cristina Monteiro

et al.

Clinical Interventions in Aging, Journal Year: 2022, Volume and Issue: Volume 17, P. 797 - 810

Published: May 1, 2022

Abstract: Aducanumab is a monoclonal antibody selective for amyloid β (Aβ) aggregates. In June 2021, aducanumab became the first drug underlying pathophysiology of Alzheimer's disease (AD) approved by US Food and Drug Administration (FDA), under accelerated approval pathway. The decision was based on ability to remove Aβ plaques, without any evidence that clearance correlated with less cognitive or functional decline. This has generated considerable debate in scientific community, especially because results from two Phase 3 trials, EMERGE ENGAGE, were divergent and, even after post hoc analysis, data insufficient prove efficacy. Moreover, some researchers think this will be an obstacle progress also demonstrated concerns about cost its safety profile. European Medicines Agency's rejection December 2021 just brought more controversy over FDA's decision. Now, Biogen designing required confirmatory study, named ENVISION, which should complete 2026. Despite controversy, showed affect downstream tau pathology, could open doors combination therapy approach AD (anti-tau anti-amyloid drug). review summarizes clinical development until regulatory agencies' decisions, available trials AD. Keywords: anti-Aβ antibody, ARIA, Agency, Administration, protein

Language: Английский

Alzheimer disease DOI
David S. Knopman, Hélène Amieva, Ronald C. Petersen

et al.

Nature Reviews Disease Primers, Journal Year: 2021, Volume and Issue: 7(1)

Published: May 13, 2021

Language: Английский

Citations

1572
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease DOI Creative Commons
Tiantian Guo, Denghong Zhang,

Yuzhe Zeng

et al.

Molecular Neurodegeneration, Journal Year: 2020, Volume and Issue: 15(1)

Published: July 16, 2020

Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There currently no effective treatment for AD, which may be attributed part to lack of a clear underlying mechanism. Studies within last few decades provide growing evidence central role amyloid β (Aβ) and tau, as well glial contributions various molecular cellular pathways AD pathogenesis. Herein, we review recent progress with respect Aβ- tau-associated mechanisms, discuss dysfunction emphasis on neuronal receptors that mediate Aβ-induced toxicity. We also other critical factors affect pathogenesis, including genetics, aging, variables related environment, lifestyle habits, describe potential apolipoprotein E (APOE), viral bacterial infection, sleep, microbiota. Although have gained much towards understanding aspects this devastating disorder, greater commitment research mechanism, diagnostics will needed future research.

Language: Английский

Citations

723
Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup DOI Creative Commons
Clifford R. Jack,

J. Scott Andrews,

Thomas G. Beach

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(8), P. 5143 - 5169

Published: June 27, 2024

Abstract The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 single 2012 2018 to create recommendations for diagnosis characterization of disease (AD). present document updates research framework response several recent developments. Defining diseases biologically, rather than based syndromic presentation, has long been standard many areas medicine (e.g., oncology), is becoming a unifying concept common all neurodegenerative diseases, not just AD. consistent with this principle. Our intent objective criteria staging AD, incorporating advances biomarkers, serve as bridge between clinical care. These are intended provide step‐by‐step practice guidelines workflow or specific treatment protocols, but general principles inform AD that reflect current science. Highlights We define (AD) be biological process begins appearance neuropathologic change (ADNPC) while people asymptomatic. Progression burden leads later progression symptoms. Early‐changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid accurate plasma [especially phosphorylated tau 217]) map onto either amyloid beta tauopathy pathway; however, these presence ADNPC more generally (i.e., both neuritic plaques tangles). An abnormal biomarker result sufficient establish decision making throughout continuum. Later‐changing 2 (biofluid PET) can prognostic information, when abnormal, will increase confidence contributing integrated scheme described accommodates fact copathologies, cognitive reserve, resistance may modify relationships stages.

Language: Английский

Citations

598
Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease DOI Creative Commons
Stephen Salloway,

Spyros Chalkias,

Frederik Barkhof

et al.

JAMA Neurology, Journal Year: 2021, Volume and Issue: 79(1), P. 13 - 13

Published: Nov. 22, 2021

The EMERGE and ENGAGE phase 3 randomized clinical trials of aducanumab provide a robust data set to characterize amyloid-related imaging abnormalities (ARIA) that occur with treatment aducanumab, an amyloid-β (Aβ)-targeting monoclonal antibody, in patients mild cognitive impairment due Alzheimer disease or dementia. To describe the radiographic characteristics ARIA occurred ENGAGE. Secondary analysis from trials, which were 2 double-blind, placebo-controlled, parallel-group, compared low-dose high-dose placebo among participants at 348 sites across 20 countries. Enrollment August 2015 July 2018, terminated early (March 21, 2019) based on futility analysis. combined studies consisted total 3285 who received 1 more doses (n = 1087) 2198; 2752 person-years exposure) during placebo-controlled period. Primary analyses performed November 2019 2020, additional through 2021. Participants randomly assigned 1:1:1 intravenous once every 4 weeks. Dose titration was used as risk-minimization strategy. Brain magnetic resonance monitor for ARIA; associated symptoms reported adverse events. Of included participants, mean (SD) age 70.4 (7.45) years; 1706 (52%) female, 2661 (81%) had disease, 1777 (54%) symptomatic medications disease. A 764 709 categorized withdrawn before study completion, most often owing termination by sponsor. Unless otherwise specified, all results represent 10-mg/kg group. During period, 425 1029 (41.3%) experienced ARIA, serious cases occurring 14 (1.4%). ARIA-edema (ARIA-E) common event (362 [35.2%]), 263 initial events (72.7%) within first 8 aducanumab; 94 (26.0%) exhibited symptoms. Common 103 ARIA-E ARIA-H headache (48 [46.6%]), confusion (15 [14.6%]), dizziness (11 [10.7%]), nausea (8 [7.8%]). Incidence highest aducanumab-treated apolipoprotein E ε4 allele carriers. Most (479 488 [98.2%]) those resolved radiographically; 404 (82.8%) 16 In group, 29 1076 (2.7%) (apolipoprotein carriers: 742 [2.2%]; noncarriers, 13 334 [3.9%]). ARIA-microhemorrhage ARIA-superficial siderosis 197 (19.1%) 151 (14.7%), respectively. this integrated safety ENGAGE, group ARIA-E, 362 (35.2%) least postbaseline MRI scan, experiencing symptom headache. ClinicalTrials.gov Identifiers: NCT02484547, NCT02477800.

Language: Английский

Citations

453
The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI–neuropathology diagnostic accuracy study DOI Creative Commons
Andreas Charidimou, Grégoire Boulouis, Matthew P. Frosch

et al.

The Lancet Neurology, Journal Year: 2022, Volume and Issue: 21(8), P. 714 - 725

Published: July 13, 2022

Language: Английский

Citations

411
The probabilistic model of Alzheimer disease: the amyloid hypothesis revised DOI
Giovanni B. Frisoni, Daniele Altomare, Dietmar Rudolf Thal

et al.

Nature reviews. Neuroscience, Journal Year: 2021, Volume and Issue: 23(1), P. 53 - 66

Published: Nov. 23, 2021

Language: Английский

Citations

346
Applications of focused ultrasound in the brain: from thermoablation to drug delivery DOI
Ying Meng, Kullervo Hynynen, Nir Lipsman

et al.

Nature Reviews Neurology, Journal Year: 2020, Volume and Issue: 17(1), P. 7 - 22

Published: Oct. 26, 2020

Language: Английский

Citations

334
Microglia use TAM receptors to detect and engulf amyloid β plaques DOI
Youtong Huang, Kaisa E. Happonen,

Patrick Burrola

et al.

Nature Immunology, Journal Year: 2021, Volume and Issue: 22(5), P. 586 - 594

Published: April 15, 2021

Language: Английский

Citations

326
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 DOI Creative Commons

Linda Söderberg,

Malin Johannesson,

Patrik Nygren

et al.

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

Citations

269
Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease DOI Creative Commons
Nils Korte, Ross Nortley, David Attwell

et al.

Acta Neuropathologica, Journal Year: 2020, Volume and Issue: 140(6), P. 793 - 810

Published: Aug. 31, 2020

Abstract Therapies targeting late events in Alzheimer’s disease (AD), including aggregation of amyloid beta (Aβ) and hyperphosphorylated tau, have largely failed, probably because they are given after significant neuronal damage has occurred. Biomarkers suggest that the earliest event AD is a decrease cerebral blood flow (CBF). This caused by constriction capillaries contractile pericytes, evoked oligomeric Aβ. CBF also reduced neutrophil trapping clot formation, perhaps secondary to capillary constriction. The fall potentiates neurodegeneration upregulating BACE1 enzyme makes Aβ promoting tau hyperphosphorylation. Surprisingly, therefore, reduction may play crucial role driving cognitive decline initiating cascade itself, or being amplifying production. Here, we review developments this area neglected current approaches AD, with aim novel mechanism-based therapeutic approaches.

Language: Английский

Citations

267