Anti-Amyloid Monoclonal Antibodies are Transformative Treatments that Redefine Alzheimer's Disease Therapeutics

Drugs, Год журнала: 2023, Номер 83(7), С. 569 - 576

Опубликована: Апрель 15, 2023

Two anti-amyloid monoclonal antibodies (MABs)—lecanemab (Leqembi®) and aducanumab (Aduhelm®)—have been approved in the USA for treatment of Alzheimer's disease (AD). Anti-amyloid are first disease-modifying therapies AD that achieve slowing clinical decline by intervening basic biological processes disease. These breakthrough agents can slow inevitable progression into more severe cognitive impairment. The results trials MABs support amyloid hypothesis as a target drug development. success reflects relentless application neuroscience knowledge to solving major challenges facing humankind. these transformative will foster development MABs, other types therapies, treatments targets biology, new approaches an array neurodegenerative disorders. Monoclonal have side effects and, during period initiation, patients must be closely monitored occurrence amyloid-related imaging abnormalities (ARIA) infusion reactions. A successful step therapy defines desirable features next phase therapeutic including less frequent ARIA, convenient administration, greater efficacy. Unprecedented make demands on care partners, clinicians, payers, health systems. Collaboration among stakeholders is essential take advantage benefits offered them widely available. usher era define landscape what possible

Язык: Английский

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Mouse Models of Alzheimer’s Disease

Frontiers in Molecular Neuroscience, Год журнала: 2022, Номер 15

Опубликована: Июнь 21, 2022

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, eventually leading to dementia. The pathological hallmarks of AD are senile plaques neurofibrillary tangles, which comprise abnormally aggregated β-amyloid peptide (Aβ) hyperphosphorylated tau protein. To develop preventive, diagnostic, therapeutic strategies for AD, it essential establish animal models that recapitulate the pathophysiological process AD. In this review, we will summarize advantages limitations various mouse including transgenic, knock-in, injection based on Aβ tau. We also discuss other neuroinflammation because recent genetic studies have suggested microglia crucial in pathogenesis Although each model has its disadvantages, further research pathobiology lead establishment more accurate models, accelerate development innovative therapeutics.

Язык: Английский

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Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics

Brain, Год журнала: 2023, Номер 146(11), С. 4414 - 4424

Опубликована: Июнь 6, 2023

Abstract Excess accumulation and aggregation of toxic soluble insoluble amyloid-β species in the brain are a major hallmark Alzheimer’s disease. Randomized clinical trials show reduced deposits using monoclonal antibodies that target have identified MRI signal abnormalities called amyloid-related imaging (ARIA) as possible spontaneous or treatment-related adverse events. This review provides comprehensive state-of-the-art conceptual radiological features, detection classification challenges, pathophysiology, underlying biological mechanism(s) risk factors/predictors associated with ARIA. We summarize existing literature current lines evidence ARIA-oedema/effusion (ARIA-E) ARIA-haemosiderosis/microhaemorrhages (ARIA-H) seen across anti-amyloid therapeutic development. Both forms ARIA may occur, often early, during anti-amyloid-β antibody treatment. Across randomized controlled trials, most cases were asymptomatic. Symptomatic ARIA-E occurred at higher doses resolved within 3–4 months upon treatment cessation. Apolipoprotein E haplotype dosage factors for ARIA-H. Presence any microhaemorrhage on baseline increases shares many clinical, pathophysiological features disease cerebral amyloid angiopathy. There is great need to conceptually link evident synergistic interplay such conditions allow clinicians researchers further understand, deliberate investigate combined effects these multiple processes. Moreover, this article aims better assist (either observed via symptoms visually MRI), management based appropriate use recommendations, general preparedness awareness when well fundamental understanding various development their risks To facilitate practice, we recommend implementation standardized protocols rigorous reporting standards. With availability approved therapies clinic, monitoring required effectively detect, monitor, manage real-world settings.

Язык: Английский

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Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Авг. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

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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Microbiota from Alzheimer’s patients induce deficits in cognition and hippocampal neurogenesis

Brain, Год журнала: 2023, Номер 146(12), С. 4916 - 4934

Опубликована: Окт. 18, 2023

Alzheimer's disease is a complex neurodegenerative disorder leading to decline in cognitive function and mental health. Recent research has positioned the gut microbiota as an important susceptibility factor by showing specific alterations microbiome composition of patients rodent models. However, it unknown whether are causal manifestation symptoms. To understand involvement patient host physiology behaviour, we transplanted faecal from age-matched healthy controls into microbiota-depleted young adult rats. We found impairments behaviours reliant on hippocampal neurogenesis, essential process for certain memory functions mood, resulting transplants. Notably, severity correlated with clinical scores donor patients. Discrete changes rat caecal metabolome were also evident. As neurogenesis cannot be measured living humans but modulated circulatory systemic environment, assessed impact environment proxy readouts. Serum decreased human cells vitro associated key microbial genera. Our findings reveal first time, that symptoms can transferred organism via microbiota, confirming role disease, highlight converging central cellular regulating gut-mediated factors Alzheimer's.

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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If amyloid drives Alzheimer disease, why have anti-amyloid therapies not yet slowed cognitive decline?

PLoS Biology, Год журнала: 2022, Номер 20(7), С. e3001694 - e3001694

Опубликована: Июль 21, 2022

Strong genetic evidence supports an imbalance between production and clearance of amyloid β-protein (Aβ) in people with Alzheimer disease (AD). Microglia that are potentially involved alternative mechanisms actually integral to the cascade. Fluid biomarkers brain imaging place accumulation Aβ at beginning molecular clinical changes disease. So why have trials anti-amyloid therapies not provided clear-cut benefits patients AD? Can robustly decrease human brain, if so, could this lowering be too little, late? These central questions research on AD being urgently addressed.

Язык: Английский

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Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer’s disease

Cell Reports, Год журнала: 2022, Номер 40(8), С. 111280 - 111280

Опубликована: Авг. 1, 2022

Dysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer's disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal healthy brain, their involvement hyperactivity AD is unknown. We show increased FC human cingulate cortex several years before amyloid deposition. find same disruption AppNL-F mice. Crucially, these disruptions are accompanied by decreased astrocyte calcium signaling. Recovery astrocytic normalizes FC, as well seizure susceptibility day/night behavioral disruptions. In conclusion, we that astrocytes mediate initial features drive clinically relevant phenotypes.

Язык: Английский

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Exercise suppresses neuroinflammation for alleviating Alzheimer’s disease

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Март 19, 2023

Abstract Alzheimer’s disease (AD) is a chronic neurodegenerative disease, with the characteristics of neurofibrillary tangle (NFT) and senile plaque (SP) formation. Although great progresses have been made in clinical trials based on relevant hypotheses, these studies are also accompanied by emergence toxic side effects, it an urgent task to explore underlying mechanisms for benefits prevent treat AD. Herein, animal experiments few trials, neuroinflammation AD characterized long-term activation pro-inflammatory microglia NOD-, LRR- pyrin domain-containing protein 3 (NLRP3) inflammasomes. Damaged signals from periphery within brain continuously activate microglia, thus resulting constant source inflammatory responses. The response exacerbates endoplasmic reticulum oxidative stress which triggers microglia-dependent immune responses, ultimately leading occurrence deterioration In this review, we systematically summarized sorted out that exercise ameliorates directly indirectly regulating central nervous system promoting hippocampal neurogenesis provide new direction exploring activity

Язык: Английский

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