Donanemab in Early Symptomatic Alzheimer Disease

JAMA, Год журнала: 2023, Номер 330(6), С. 512 - 512

Опубликована: Июль 17, 2023

Importance There are limited efficacious treatments for Alzheimer disease. Objective To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, Setting, Participants Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic disease (mild cognitive impairment/mild dementia) low/medium or high tau pathology based on positron emission tomography imaging from June 2020 November 2021 (last patient visit primary outcome April 2023). Interventions were randomized a 1:1 ratio receive donanemab (n = 860) placebo 876) intravenously every 4 weeks 72 weeks. the group switched blinded manner if dose completion criteria met. Main Outcomes Measures The was change integrated Disease Rating Scale (iADRS) score baseline 76 (range, 0-144; lower scores indicate greater impairment). 24 gated outcomes (primary, secondary, exploratory), including secondary sum boxes Clinical Dementia (CDR-SB) 0-18; higher Statistical testing allocated α .04 population outcomes, remainder (.01) combined outcomes. Results Among (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] 552 [31.8%] pathology), 1320 (76%) completed trial. Of 23 statistically significant. least-squares mean (LSM) iADRS at −6.02 (95% CI, −7.01 −5.03) −9.27 −10.23 −8.31) (difference, 3.25 [95% 1.88-4.62]; P < .001) −10.2 −11.22 −9.16) −13.1 −14.10 −12.13) 2.92 1.51-4.33]; population. LSM CDR-SB 1.20 1.00-1.41) 1.88 1.68-2.08) −0.67 −0.95 −0.40]; 1.72 1.53-1.91) 2.42 2.24-2.60) −0.7 −0.45]; Amyloid-related abnormalities edema effusion occurred 205 (24.0%; 52 symptomatic) 18 (2.1%; 0 during study) infusion-related reactions 74 (8.7%) (0.5%) placebo. Three deaths 1 considered treatment related. Conclusions Relevance pathology, significantly slowed clinical progression those Trial Registration ClinicalTrials.gov Identifier: NCT04437511

Язык: Английский

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Alzheimer's disease: From immunotherapy to immunoprevention

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

Опубликована: Сен. 1, 2023

Язык: Английский

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Anti-Amyloid Monoclonal Antibodies for the Treatment of Alzheimer’s Disease

BioDrugs, Год журнала: 2023, Номер 38(1), С. 5 - 22

Опубликована: Ноя. 13, 2023

Two monoclonal antibodies (mAbs), aducanumab and lecanemab, have received accelerated approval from the US FDA for initiation of treatment in early Alzheimer's disease patients who proven β-amyloid pathology (Aβ). One these, has subsequently full other are poised positive review approval. Anti-amyloid mAbs share feature producing a marked reduction total brain Aβ revealed by amyloid positron emission tomography. Trials associated with slowing cognitive decline achieved measurable plaque range 15–25 centiloids; trials agents that did not reach this threshold were benefit. differences terms titration schedules, MRI monitoring schedules amyloid-related imaging abnormalities (ARIA), continuing versus interrupted therapy. The approximate 30% observed is clinically meaningful extended integrity delay onset more severe dementia phases disease. Approval these initiates new era therapeutics disease-modifying properties. Further advances needed, i.e. greater efficacy, improved safety, enhanced convenience, better understanding ill-understood observations such as volume loss.

Язык: Английский

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The amyloid cascade hypothesis: an updated critical review

Brain, Год журнала: 2023, Номер 146(10), С. 3969 - 3990

Опубликована: Май 15, 2023

Results from recent clinical trials of antibodies that target amyloid-β (Aβ) for Alzheimer's disease have created excitement and been heralded as corroboration the amyloid cascade hypothesis. However, while Aβ may contribute to disease, genetic, clinical, imaging biochemical data suggest a more complex aetiology. Here we review history weaknesses hypothesis in view new evidence obtained anti-amyloid antibodies. These indicate treatments either no or uncertain effect on cognition. Despite importance definition argue point playing minor aetiological role. We also discuss suggesting concerted activity many pathogenic factors propose evolving multi-factor models will better underpin search effective strategies treat disease.

Язык: Английский

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Fatal iatrogenic cerebral β-amyloid-related arteritis in a woman treated with lecanemab for Alzheimer’s disease

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Дек. 12, 2023

We report the case of a 79-year-old woman with Alzheimer's disease who participated in Phase III randomized controlled trial called CLARITY-AD testing experimental drug lecanemab. She was to placebo group and subsequently enrolled an open-label extension which guaranteed she received active drug. After third biweekly infusion, suffered seizure characterized by speech arrest generalized convulsion. Magnetic resonance imaging revealed had multifocal swelling marked increase number cerebral microhemorrhages. treated antiepileptic regimen high-dose intravenous corticosteroids but continued worsen died after 5 days. Post-mortem MRI confirmed extensive microhemorrhages temporal, parietal occipital lobes. The autopsy presence two copies APOE4, gene associated higher risk disease, neuropathological features moderate severity severe amyloid angiopathy perivascular lymphocytic infiltrates, reactive macrophages fibrinoid degeneration vessel walls. There were deposits β-amyloid meningeal vessels penetrating arterioles numerous microaneurysms. conclude that patient likely as result amyloid-related inflammation.

Язык: Английский

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Oxidative Stress Occurs Prior to Amyloid Aβ Plaque Formation and Tau Phosphorylation in Alzheimer’s Disease: Role of Glutathione and Metal Ions

ACS Chemical Neuroscience, Год журнала: 2023, Номер 14(17), С. 2944 - 2954

Опубликована: Авг. 10, 2023

Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disorder that affects millions of people worldwide. Although the pathogenesis remains obscure, there are two dominant causal hypotheses. Since last three decades, amyloid beta (Aβ) deposition was most prominent hypothesis, other tau hyperphosphorylation hypothesis. The confirmed diagnostic criterion for AD presence neurofibrillary tangles (NFTs) composed hyperphosphorylated toxic oligomeric Aβ in autopsied brain. Consistent with these hypotheses, oxidative stress (OS) garnering major attention research. OS results from imbalance pro-oxidants antioxidants. There a considerable debate scientific community on which process occurs first, or plaque deposition/tau hyperphosphorylation. Based recent observations various laboratories including ours along critical analysis those information, we believe early event leads to as well dimerization protein its subsequent This hypothesis immediately suggests consideration novel therapeutic approaches include antioxidants involving glutathione enrichment brain by supplementation without iron chelator.

Язык: Английский

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Ferroptosis in health and disease

Redox Biology, Год журнала: 2024, Номер 75, С. 103211 - 103211

Опубликована: Май 30, 2024

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark ferroptosis uncontrolled overwhelming peroxidation polyunsaturated fatty acids contained membrane phospholipids, which eventually leads to rupture the plasma membrane. unique that it essentially spontaneous, uncatalyzed chemical process based on perturbed iron redox homeostasis contributing process, but nonetheless modulated by many metabolic nodes impinge cells' susceptibility ferroptosis. Among affecting sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets treatment numerous currently incurable diseases. Herein, current members Germany-wide research consortium focusing research, well key external experts who made seminal contributions this rapidly growing exciting field gathered provide comprehensive, state-of-the-art review Specific topics include: basic mechanisms, vivo relevance, specialized methodologies, tools, potential contribution disease etiopathology progression. We hope article will not only established scientists newcomers with an overview multiple facets ferroptosis, also encourage additional efforts characterize further molecular pathways modulating ultimate goal develop novel pharmacotherapies tackle associated - or caused

Язык: Английский

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Passive immunotherapy for Alzheimer's disease

Ageing Research Reviews, Год журнала: 2024, Номер 94, С. 102192 - 102192

Опубликована: Янв. 14, 2024

Alzheimer's disease (AD) is the most common neurodegenerative characterized by cognitive impairment with few therapeutic options. Despite many failures in developing AD treatment during past 20 years, significant advances have been achieved passive immunotherapy of very recently. Here, we review characteristics, clinical trial data, and mechanisms action for monoclonal antibodies (mAbs) targeting key players pathogenesis, including amyloid-β (Aβ), tau neuroinflammation modulators. We emphasized efficacy lecanemab donanemab on cognition amyloid clearance patients phase III trials discussed factors that may contribute to side effects anti-Aβ mAbs. In addition, provided important information mAbs or inflammatory regulators trials, indicated against mid-region pathogenic potential AD. conclusion, pathogenesis offers a promising strategy effective treatment.

Язык: Английский

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Lecanemab and Donanemab as Therapies for Alzheimer's Disease: An Illustrated Perspective on the Data

eNeuro, Год журнала: 2024, Номер 11(7), С. ENEURO.0319 - 23.2024

Опубликована: Июль 1, 2024

Язык: Английский

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Loss of monomeric alpha-synuclein (synucleinopenia) and the origin of Parkinson's disease

Parkinsonism & Related Disorders, Год журнала: 2024, Номер 122, С. 106077 - 106077

Опубликована: Март 3, 2024

These facts argue against the gain-of-function synucleinopathy hypothesis, which proposes that Lewy pathology causes Parkinson's disease: (1) most brains from people without neurological symptoms have multiple pathologies; (2) neither type nor distribution correlate with disease severity or progression in disease; (3) aggregated α-synuclein form of bodies is not a space-occupying lesion but insoluble fraction its precursor, soluble monomeric α-synuclein; (4) spread passive, occurring by irreversible nucleation, active replication; and (5) low cerebrospinal fluid levels predict brain atrophy clinical progression. The transformation into may occur as response to biological, toxic, infectious stressors whose persistence perpetuates nucleation process, depleting normal eventually leading neuronal death. We propose testing loss-of-function synucleinopenia hypothesis evaluating neurodegenerative rescue effect replenishing α-synuclein.

Язык: Английский

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