N-terminal-targeted anti-amyloid monoclonal antibodies illuminate the therapy for Alzheimer’s disease: a systematic review and comprehensive meta-analysis DOI Open Access

Yuhui Qiu,

Ming Liu, Jie Zhan

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Ноя. 22, 2023

Summary Background Recent clinical trials of anti-amyloid-beta (Aβ) monoclonal antibodies (mAbs) have demonstrated that the removal Aβ in symptomatic patients can slow down progression Alzheimer’s disease (AD) and reinforce “amyloid cascade” hypothesis. However, further investigation analysis integrated data is needed to interpret efficacy these mAbs. In this study, we aimed estimate effectiveness mAbs for AD firstly assessed therapeutic from a perspective targeting specific domains (N-terminal, C-terminal, central domain, N-terminal+central domain) pre-specified subgroups. Methods systematic review meta-analysis, searched on Pubmed, Embase, Cochrane Library, ClinicalTrials.gov their inception until 31 August, 2023, updated our search 15 October, identify all published randomised controlled (RCTs) various outcomes anti-Aβ AD. The primary interest included Disease Assessment Scale-cognitive subscale (ADAS-cog), Mini Mental State Examination (MMSE), Clinical Dementia Rating scale-Sum Boxes (CDR-SB), as well amyloid positron emission tomography (PET), main biomarker. Additionally, collected volumetric Magnetic Resonance Imaging (vMRI), cerebrospinal fluid (CSF), plasma biomarkers, risks amyloid-related imaging abnormalities (ARIA). Random-effects models calculate pooled risk ratios (RRs) standardized mean differences (SMDs) were employed analyze across multiple studies Furthermore, also examined interrelationships among changes alterations cognitive performance, deposition, variations ARIA both N-terminal-targeted by calculating Pearson’s correlation coefficients. This study registered with PROSPERO, No. CRD42023430637. Findings We identified total 37 eligible quality assessment, which 34 meta-analysis. revealed eight (aducanumab, lecanemab, donanemab, bapineuzumab, gantenerumab, crenezumab, solanezumab, ponezumab) statistical improvements outcomes. Specifically, ADAS-cog [(total mAbs: SMD: -0.08, 95% CI: -0.11 -0.04); (N-terminal-targeted -0.13 -0.03)], CDR-SB -0.06, -0.12 -0.00); -0.16 -0.01)], MMSE 0.06, 0.02 0.10); 0.05, -0.00 0.10)] significant improvement. addition, meta-analyses indicated had statistically impact reducing PET -1.13, -1.66 -0.61); -1.64, -2.27 -1.02)], accelerating ventricle enlargement 0.22, 0.06 0.38); 0.44, 0.30 0.57)], causing whole-brain atrophy -0.14, -0.26 -0.03); -0.24, -0.41 -0.07)], while increased ARIA-E (total RR: 9.79, CI 7.83 12.26); 10.79, 8.61 13.52)] ARIA-H 1.28, 0.98 1.67); 1.94, 1.64 2.29)]. no hippocampal volume was observed 0.00, -0.07 0.07); -0.03, 0.07)]. It should be noted above effects more treated mAbs, subgroup analyses. negative association between ventricular clearance (Pearson’s r: -0.76), especially administration -0.79), indicating stronger effect clearance. Moreover, there strong improvement function preservation -0.70), particularly case Lastly, found reduction -0.60), brain -0.83), 0.92). Interpretation specifically target N-terminus showed promising results burden ameliorating decline. preliminary findings shed light occurrence atrophy, enlargement, ARIA, might attributed deposits caused mAb administration. future development, meta-analysis an optimizing approach. Funding work supported National Natural Science Foundation China (No. 82004430, 82174310). Research context Evidence before recent lecanemab donanemab provided initial conclusive evidences patients’ brains decelerate (AD). These offer substantiation significance aberrant pathogenesis, thereby reinforcing validity "amyloid cascade" While, benefit still limited it important note subjects are experienced progression, albeit at slower rate. Targeting forms (monomers, oligomers, fibrils) considered key mechanism mAbs’ efficacy. not crucial direction explain ideal antibody order discover underlying mechanisms formulate enhanced immunotherapeutic regimen, essential trials. Added value comprehensive only encompassed reported RCTs investigating AD, but N-terminal+central-domain, central-domain, C-terminal) Enhanced syntheses enhancements (ADAS-cog, MMSE) utilization significantly reduced certain expedited concurrently ARIA. notable using Aβ, evidenced analyses employing different epitopes Aβ. Association positive extent deposition after therapy degree function, supporting plaques pivotal driver decline emphasizing advantages associated elimination brain. Further, possible or clearance, Improvement seemed related volume. strongly correlated reductions enlargement. Hence, us recognize clearing crucial. Nevertheless, exacerbation cerebral higher severity great abilities Implications available evidence support patients, represented potentially groundbreaking strategy. principle “structure dictates function” guiding tenet N-terminal region design superior future.

Язык: Английский

Alzheimer's disease: From immunotherapy to immunoprevention DOI Creative Commons
Mathias Jucker, Lary C. Walker

Cell, Год журнала: 2023, Номер 186(20), С. 4260 - 4270

Опубликована: Сен. 1, 2023

Язык: Английский

Процитировано

125
Amyloid-Targeting Monoclonal Antibodies for Alzheimer Disease DOI Open Access
Gil D. Rabinovici, Renaud La Joie

JAMA, Год журнала: 2023, Номер 330(6), С. 507 - 507

Опубликована: Июль 17, 2023

Our website uses cookies to enhance your experience. By continuing use our site, or clicking "Continue," you are agreeing Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals Network Open Cardiology Dermatology Health Forum Internal Medicine Neurology Oncology Ophthalmology Otolaryngology–Head & Neck Surgery Pediatrics Psychiatry Archives of (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions LibrariansReprints Permissions Terms Use Privacy Accessibility Statement 2023 American Association. All Rights Reserved Search Archive Input Term Sign In Individual inCreate an Account Access through institution Purchase Options: Buy this article Rent Subscribe the journal

Язык: Английский

Процитировано

42
Second-generation anti-amyloid monoclonal antibodies for Alzheimer’s disease: current landscape and future perspectives DOI Creative Commons

Byeong‐Hyeon Kim,

Sujin Kim, Yunkwon Nam

и другие.

Translational Neurodegeneration, Год журнала: 2025, Номер 14(1)

Опубликована: Янв. 27, 2025

Abstract Alzheimer’s disease (AD) is the most common type of dementia. Monoclonal antibodies (MABs) serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors, such amyloid-β (Aβ) peptide, tau protein, and neuroinflammation. Specifically, based on their efficacy in removing Aβ plaques from brains patients with AD, U.S. Food Drug Administration has approved three anti-amyloid MABs, aducanumab (Aduhelm®), lecanemab (Leqembi®), donanemab (Kisunla™). Notably, received traditional approval after demonstrating clinical benefit, supporting cascade hypothesis. These MABs are categorized affinity to diverse conformational features Aβ, including monomer, fibril, protofibril, plaque forms well pyroglutamate Aβ. First-generation non-toxic monomeric solanezumab, bapineuzumab, crenezumab, failed demonstrate benefit trials. In contrast, second-generation aducanumab, lecanemab, donanemab, gantenerumab directed against species aggregates have shown that reducing deposition can be an effective strategy slow cognitive impairment AD. this review, we provide comprehensive overview current status, mechanisms, outcomes, limitations treatment Moreover, discuss perspectives future directions

Язык: Английский

Процитировано

4
Brain volume change following anti-amyloid β immunotherapy for Alzheimer's disease: amyloid-removal-related pseudo-atrophy DOI
Christopher R S Belder, Delphine Boche, James A. R. Nicoll

и другие.

The Lancet Neurology, Год журнала: 2024, Номер 23(10), С. 1025 - 1034

Опубликована: Сен. 19, 2024

Язык: Английский

Процитировано

11
Biomarker treatment effects in two phase 3 trials of gantenerumab DOI Creative Commons
Tobias Bittner, Mattéo Tonietto,

Gregory Klein

и другие.

Alzheimer s & Dementia, Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

Abstract INTRODUCTION We report biomarker treatment effects in the GRADUATE I and II phase 3 studies of gantenerumab early Alzheimer's disease (AD). METHODS Amyloid tau positron emission tomography (PET), volumetric magnetic resonance imaging (vMRI), cerebrospinal fluid (CSF), plasma biomarkers used to assess related changes on neuropathology, neurodegeneration, neuroinflammation over 116 weeks. RESULTS Gantenerumab reduced amyloid PET load, CSF beta (Aβ)40, total (t‐tau), phosphorylated 181 (p‐tau181), neurogranin, S100 calcium‐binding protein B (S100B), neurofilament light (NfL), alpha‐synuclein (α‐syn), neuronal pentraxin‐2 (NPTX2), t‐tau, p‐tau181, p‐tau217, glial fibrillary acidic (GFAP) while increasing Aβ40, Aβ42. vMRI showed increased reduction whole brain volume ventricular expansion, hippocampal was unaffected. Tau no effect. DISCUSSION Robust were observed for multiple II. Comparison across anti‐amyloid antibodies indicates utility p‐tau GFAP as plaque removal NfL seem unsuitable consistent indicators clinical efficacy. might be confounded by non‐neurodegenerative changes. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV IDENTIFIER) : NCT03444870 NCT03443973. Highlights significantly load. effect a small subset participants. Volumetric under found, despite lack

Язык: Английский

Процитировано

1
Amyloid-Related Imaging Abnormalities in the Era of Anti-Amyloid Beta Monoclonal Antibodies for Alzheimer’s Disease: Recent Updates on Clinical and Imaging Features and MRI Monitoring DOI
So Yeong Jeong, Chong Hyun Suh, Sang Joon Kim

и другие.

Korean Journal of Radiology, Год журнала: 2024, Номер 25(8), С. 726 - 726

Опубликована: Янв. 1, 2024

Recent advancements in Alzheimer's disease treatment have focused on the elimination of amyloid-beta (Aβ) plaque, a hallmark disease. Monoclonal antibodies such as lecanemab and donanemab can alter progression by binding to different forms Aβ aggregates. However, these treatments raise concerns about adverse effects, particularly amyloid-related imaging abnormalities (ARIA). Careful assessment safety, especially regarding ARIA, is crucial. ARIA results from treatment-related disruption vascular integrity increased permeability, leading leakage proteinaceous fluid (ARIA-E) heme products (ARIA-H). ARIA-E indicates treatment-induced edema or sulcal effusion, while ARIA-H microhemorrhage superficial siderosis. The minimum recommended magnetic resonance sequences for are T2-FLAIR, T2* gradient echo (GRE), diffusion-weighted (DWI). T2-FLAIR GRE necessary detect ARIA-H, respectively. DWI plays role differentiating acute subacute infarcts. Physicians, including radiologists, must be familiar with features appropriate protocol workup, reporting findings clinical practice. This review aims describe suggest points timely detection monitoring

Язык: Английский

Процитировано

7
Scanning ultrasound-mediated memory and functional improvements do not require amyloid-β reduction DOI Creative Commons
Gerhard Leinenga, Xuan Vinh To, Liviu‐Gabriel Bodea

и другие.

Molecular Psychiatry, Год журнала: 2024, Номер 29(8), С. 2408 - 2423

Опубликована: Март 18, 2024

Abstract A prevalent view in treating age-dependent disorders including Alzheimer’s disease (AD) is that the underlying amyloid plaque pathology must be targeted for cognitive improvements. In contrast, we report here repeated scanning ultrasound (SUS) treatment at 1 MHz frequency can ameliorate memory deficits APP23 mouse model of AD without reducing amyloid-β (Aβ) burden. Different from previous studies had shown Aβ clearance as a consequence blood-brain barrier (BBB) opening, here, BBB was not opened no microbubbles were used. Quantitative SWATH proteomics and functional magnetic resonance imaging revealed induced long-lasting changes correlate with improvement memory. Intriguingly, more effective higher (1 MHz) than within range currently explored clinical trials patients (286 kHz). Together, our data suggest frequency-dependent bio-effects dissociation clearance, important implications design therapies.

Язык: Английский

Процитировано

6
Implications of the Approval of Lecanemab for Alzheimer Disease Patient Care DOI
David S. Knopman, Linda A. Hershey

Neurology, Год журнала: 2023, Номер 101(14), С. 610 - 620

Опубликована: Июнь 9, 2023

The amyloid cascade model of the pathogenesis Alzheimer disease (AD) is well supported in observational studies. Its therapeutic corollary asserts that removal amyloid-β peptide ("amyloid") would provide clinical benefits. After 2 decades pursuing strategy without success, trials antiamyloid monoclonal antibody (AAMA) donanemab and a phase 3 trial lecanemab have reported benefits linked to removal. Lecanemab (trade name, Leqembi) first with published results. When administered through IV every weeks patients elevated brain mild cognitive impairment or dementia, delayed functional worsening by approximately 5 months an 18-month double-blind, placebo-controlled trial. was conducted, results favoring were internally consistent. demonstration treatment progression persons symptoms due AD major conceptual achievement, but better appreciation magnitude durability for individual will require extended observations from practice settings. Amyloid-related imaging abnormalities (ARIA) largely asymptomatic occurred 20%, slightly more than half which attributable rest underlying AD-related angiopathy. Persons who homozygous

Язык: Английский

Процитировано

15
Conveying Risks of Harm in Alzheimer Disease by Amyloid Lowering DOI
Madhav Thambisetty, Robert Howard

JAMA, Год журнала: 2024, Номер 331(23), С. 1985 - 1985

Опубликована: Май 6, 2024

This Viewpoint discusses how data gaps in published research impede clinicians’ ability to clearly discuss the risks and benefits of amyloid-lowering drugs for treating Alzheimer disease.

Язык: Английский

Процитировано

5
Simufilam Reverses Aberrant Receptor Interactions of Filamin A in Alzheimer’s Disease DOI Open Access

Hoau-Yan Wang,

Erika Cecon, Julie Dam

и другие.

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(18), С. 13927 - 13927

Опубликована: Сен. 11, 2023

Simufilam is a novel oral drug candidate in Phase 3 clinical trials for Alzheimer's disease (AD) dementia. This small molecule binds an altered form of filamin A (FLNA) that occurs AD. action disrupts FLNA's aberrant linkage to the α7 nicotinic acetylcholine receptor (α7nAChR), thereby blocking soluble amyloid beta1-42 (Aβ42)'s signaling via α7nAChR hyperphosphorylates tau. Here, we aimed clarify simufilam's mechanism. We now show simufilam reduced Aβ42 binding with 10-picomolar IC50 using time-resolved fluorescence resonance energy transfer (TR-FRET), robust technology detect highly sensitive molecular interactions. also FLNA links multiple inflammatory receptors addition Toll-like 4 (TLR4) postmortem human AD brains and transgenic mice: TLR2, C-X-C chemokine type (CXCR4), C-C 5 (CCR5), T-cell co-receptor cluster differentiation (CD4). These linkages, which can be induced healthy control brain by incubation, were disrupted simufilam. cytokine release from Aβ42-stimulated astrocytes. In mice, CCR5-G protein coupling was elevated, indicating persistent activation. Oral both FLNA-CCR5 these while restoring CCR5's responsivity ligand (CCL3). By disrupting FLNA-receptor interactions critical pathogenic pathways, may promote health.

Язык: Английский

Процитировано

11