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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New clinical trial design in precision medicine: discovery, development and direction

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

Опубликована: Март 4, 2024

Abstract In the era of precision medicine, it has been increasingly recognized that individuals with a certain disease are complex and different from each other. Due to underestimation significant heterogeneity across participants in traditional “one-size-fits-all” trials, patient-centered trials could provide optimal therapy customization specific biomarkers were developed including basket, umbrella, platform trial designs under master protocol framework. recent years, successive FDA approval indications based on biomarker-guided demonstrated these new clinical ushering tremendous opportunities. Despite rapid increase number current research understanding designs, as compared remains limited. The majority focuses methodologies, there is lack in-depth insight concerning underlying biological logic designs. Therefore, we this comprehensive review discovery development their perspective medicine. Meanwhile, discuss future directions potential design view “Precision Pro”, “Dynamic Precision”, “Intelligent Precision”. This would assist trial-related researchers enhance innovation feasibility by expounding logic, which be essential accelerate progression

Язык: Английский

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Neuropathogenesis-on-chips for neurodegenerative diseases

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 12, 2024

Abstract Developing diagnostics and treatments for neurodegenerative diseases (NDs) is challenging due to multifactorial pathogenesis that progresses gradually. Advanced in vitro systems recapitulate patient-like pathophysiology are emerging as alternatives conventional animal-based models. In this review, we explore the interconnected pathogenic features of different types ND, discuss general strategy modelling NDs using a microfluidic chip, introduce organoid-on-a-chip next advanced relevant model. Lastly, overview how these models being applied academic industrial drug development. The integration chips, stem cells, biotechnological devices promises provide valuable insights biomedical research developing diagnostic therapeutic solutions NDs.

Язык: Английский

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Alzheimer's disease pathophysiology in the Retina

Progress in Retinal and Eye Research, Год журнала: 2024, Номер 101, С. 101273 - 101273

Опубликована: Май 15, 2024

The retina is an emerging CNS target for potential noninvasive diagnosis and tracking of Alzheimer's disease (AD). Studies have identified the pathological hallmarks AD, including amyloid β-protein (Aβ) deposits abnormal tau protein isoforms, in retinas AD patients animal models. Moreover, structural functional vascular abnormalities such as reduced blood flow, Aβ deposition, blood-retinal barrier damage, along with inflammation neurodegeneration, been described mild cognitive impairment dementia. Histological, biochemical, clinical studies demonstrated that nature severity pathologies brain correspond. Proteomics analysis revealed a similar pattern dysregulated proteins biological pathways patients, enhanced inflammatory neurodegenerative processes, impaired oxidative-phosphorylation, mitochondrial dysfunction. Notably, investigational imaging technologies can now detect AD-specific deposits, well vasculopathy neurodegeneration living suggesting alterations at different stages links to pathology. Current exploratory ophthalmic modalities, optical coherence tomography (OCT), OCT-angiography, confocal scanning laser ophthalmoscopy, hyperspectral imaging, may offer promise assessment AD. However, further research needed deepen our understanding AD's impact on its progression. To advance this field, future require replication larger diverse cohorts confirmed biomarkers standardized retinal techniques. This will validate aiding early screening monitoring.

Язык: Английский

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Disentangling tau: One protein, many therapeutic approaches

Neurotherapeutics, Год журнала: 2024, Номер 21(2), С. e00321 - e00321

Опубликована: Янв. 25, 2024

The tauopathies encompass over 20 adult neurodegenerative diseases and are characterized by the dysfunction accumulation of insoluble tau protein. Among them, Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy collectively impact millions patients their families worldwide. Despite years drug development using a variety mechanisms action, no therapeutic directed against has been approved for clinical use. This raises important questions about our current model pathology invites thoughtful consideration approach to nonclinical models trial design. In this article, we review what is known biology genetics tau, placing it in context failed trials. We highlight potential reasons lack success date offer suggestions new pathways development. Overall, viewpoint future optimistic group diseases.

Язык: Английский

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The advent of Alzheimer treatments will change the trajectory of human aging

Nature Aging, Год журнала: 2024, Номер 4(4), С. 453 - 463

Опубликована: Апрель 19, 2024

Язык: Английский

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evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer’s disease

Alzheimer s Research & Therapy, Год журнала: 2025, Номер 17(1)

Опубликована: Янв. 8, 2025

Disease-modifying therapies targeting the diverse pathophysiology of Alzheimer's disease (AD), including neuroinflammation, represent potentially important and novel approaches. The glucagon-like peptide-1 receptor agonist semaglutide is approved for treatment type 2 diabetes obesity has an established safety profile. Semaglutide may have a disease-modifying, neuroprotective effect in AD through multimodal mechanisms neuroinflammatory, vascular, other AD-related processes. Large randomized controlled trials are needed to assess efficacy early-stage symptomatic AD. evoke evoke+ randomized, double-blind, placebo-controlled phase 3 investigating efficacy, safety, tolerability once-daily oral versus placebo Eligible participants were men or women aged 55–85 years with mild cognitive impairment dementia due confirmed amyloid abnormalities (assessed by positron emission tomography cerebrospinal fluid [CSF] analysis). After maximum 12-week screening phase, anticipated 1840 patients each trial (1:1) 156 weeks (104-week main 52-week extension). Randomized follow 8-week dose escalation regimen (3 mg [weeks 0–4], 7 4–8], 14 8–156]). primary endpoint semaglutide–placebo difference on change from baseline week 104 Clinical Dementia Rating – Sum Boxes score. Analyses plasma biomarkers, collected all participants, CSF sub-study (planned n = 210) will explore effects biomarkers neuroinflammation. Enrollment was undertaken between May 18, 2021, September 8, 2023. Completion trials' expected 2025, extension (in which investigators remain blinded assignment) continue October 2026. first large-scale investigate disease-modifying potential AD, exploration provide data be evaluating its utility Clinicaltrials.gov, NCT04777396 NCT04777409. Date: 02/03/2021

Язык: Английский

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Maximizing the benefit and managing the risk of anti-amyloid monoclonal antibody therapy for Alzheimer's disease: Strategies and research directions

Neurotherapeutics, Год журнала: 2025, Номер unknown, С. e00570 - e00570

Опубликована: Март 1, 2025

Язык: Английский

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Genomic stress and impaired DNA repair in Alzheimer disease

DNA repair, Год журнала: 2024, Номер 139, С. 103678 - 103678

Опубликована: Апрель 11, 2024

Язык: Английский

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The Role of Brain-Derived Neurotrophic Factor as an Essential Mediator in Neuronal Functions and the Therapeutic Potential of Its Mimetics for Neuroprotection in Neurologic and Psychiatric Disorders

Molecules, Год журнала: 2025, Номер 30(4), С. 848 - 848

Опубликована: Фев. 12, 2025

Among neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4/5), BDNF has been extensively studied for its physiological role in cell survival synaptic regulation the central nervous system's (CNS's) neurons. binds to TrkB (a tyrosine kinase) with high affinity, resulting downstream intracellular signaling cascades play crucial roles determining fate, neuronal differentiation maturation of CNS It well demonstrated that downregulation/dysregulation BDNF/TrkB system is implicated pathogenesis neurologic psychiatric disorders, such as Alzheimer's disease (AD) depression. Interestingly, effects mimetic compounds flavonoids, small molecules which can activate TrkB-mediated signaling, have investigated potential therapeutic strategies brain diseases, given p75NTR, a common neurotrophin receptor, also contributes death under variety pathological conditions neurodegeneration. Since downregulation associated pathophysiology neurodegenerative diseases understanding how alterations contribute progression could provide valuable insight prevention these diseases. The present review shows recent advances molecular mechanisms underlying plasticity, providing critical insights into impact mimetics

Язык: Английский

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