Updates on mouse models of Alzheimer’s disease DOI Creative Commons

Michael Z Zhong,

Thomas Peng,

Mariana Lemos Duarte

и другие.

Molecular Neurodegeneration, Год журнала: 2024, Номер 19(1)

Опубликована: Март 11, 2024

Abstract Alzheimer’s disease (AD) is the most common neurodegenerative in United States (US). Animal models, specifically mouse models have been developed to better elucidate mechanisms and test therapeutic strategies for AD. A large portion of effort field was focused on developing transgenic (Tg) through over-expression genetic mutations associated with familial AD (FAD) patients. Newer generations knock-in (KI)/knock-out (KO) or CRISPR gene editing technologies, both sporadic risk genes hope more accurately model proteinopathies without human brains. In this review, we summarized phenotypes a few commonly used as well newly translational research laboratories including presence absence key pathological features such amyloid tau pathology, synaptic neuronal degeneration cognitive behavior deficits. addition, advantages limitations these elaborated along discussions any sex-specific features. More importantly, omics data from available analyzed categorize molecular signatures each reminiscent brain changes, guide future selection suitable specific questions be addressed field.

Язык: Английский

Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission DOI
Gill Livingston, Jonathan Huntley, Kathy Liu

и другие.

The Lancet, Год журнала: 2024, Номер 404(10452), С. 572 - 628

Опубликована: Июль 31, 2024

Язык: Английский

Процитировано

559
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

и другие.

Alzheimer s & Dementia, Год журнала: 2024, Номер 20(8), С. 5143 - 5169

Опубликована: Июнь 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.

Язык: Английский

Процитировано

496
Emerging diagnostics and therapeutics for Alzheimer disease DOI
Wade Self, David M. Holtzman

Nature Medicine, Год журнала: 2023, Номер 29(9), С. 2187 - 2199

Опубликована: Сен. 1, 2023

Язык: Английский

Процитировано

190
Two Phase 3 Trials of Gantenerumab in Early Alzheimer’s Disease DOI
Randall J. Bateman, Janice Smith, Michael Donohue

и другие.

New England Journal of Medicine, Год журнала: 2023, Номер 389(20), С. 1862 - 1876

Опубликована: Ноя. 15, 2023

Monoclonal antibodies that target amyloid-beta (Aβ) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody highest affinity for aggregated Aβ has been tested treatment of Download PDF Research Summary. We conducted two phase 3 trials (GRADUATE I II) involving participants 50 90 years age mild impairment or dementia due disease evidence amyloid plaques on positron-emission tomography (PET) cerebrospinal fluid (CSF) testing. Participants were randomly assigned receive gantenerumab placebo every 2 weeks. The primary outcome was change from baseline score Clinical Dementia Rating scale–Sum Boxes (CDR-SB; range, 0 18, higher scores indicating greater impairment) at week 116. A total 985 980 enrolled GRADUATE II trials, respectively. CDR-SB 3.7 trial 3.6 trial. 116 3.35 3.65 (difference, –0.31; 95% confidence interval [CI], –0.66 0.05; P=0.10) 2.82 3.01 –0.19; CI, –0.55 0.17; P=0.30). At 116, difference level PET between group –66.44 –56.46 centiloids respectively, amyloid-negative status attained 28.0% 26.8% receiving trials. Across both had lower CSF levels phosphorylated tau 181 Aβ42 than those placebo; accumulation similar groups. Amyloid-related imaging abnormalities edema (ARIA-E) occurred 24.9% gantenerumab, symptomatic ARIA-E 5.0%. Among disease, use led plaque burden weeks but not associated slower clinical decline. (Funded by F. Hoffmann–La Roche; ClinicalTrials.gov numbers, NCT03444870 NCT03443973, respectively.) QUICK TAKE VIDEO SUMMARYGantenerumab Early Disease 02:01

Язык: Английский

Процитировано

149
Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies DOI Creative Commons
Jifa Zhang, Yinglu Zhang, Jiaxing Wang

и другие.

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

Процитировано

135
Clinical trials of new drugs for Alzheimer disease: a 2020–2023 update DOI Creative Commons

Li‐Kai Huang,

Yi‐Chun Kuan,

Ho-Wei Lin

и другие.

Journal of Biomedical Science, Год журнала: 2023, Номер 30(1)

Опубликована: Окт. 2, 2023

Abstract Alzheimer's disease (AD) is the leading cause of dementia, presenting a significant unmet medical need worldwide. The pathogenesis AD involves various pathophysiological events, including accumulation amyloid and tau, neuro-inflammation, neuronal injury. Clinical trials focusing on new drugs for were documented in 2020, but subsequent developments have emerged since then. Notably, US-FDA has approved Aducanumab Lecanemab, both antibodies targeting amyloid, marking end nearly two-decade period without drugs. In this comprehensive report, we review all listed clinicaltrials.gov, elucidating their underlying mechanisms study designs. Ongoing clinical are investigating numerous promising AD. main trends these involve pathophysiology-based, disease-modifying therapies recruitment participants earlier stages disease. These underscore significance conducting fundamental research pathophysiology, prevention, intervention prior to occurrence brain damage caused by

Язык: Английский

Процитировано

133
Anti-Amyloid Monoclonal Antibodies for the Treatment of Alzheimer’s Disease DOI Creative Commons
Jeffrey L. Cummings, Amanda M. Leisgang Osse, Davis Cammann

и другие.

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

Процитировано

127
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
Tau-targeting therapies for Alzheimer disease: current status and future directions DOI
Erin E. Congdon, Changyi Ji,

Amber M. Tetlow

и другие.

Nature Reviews Neurology, Год журнала: 2023, Номер 19(12), С. 715 - 736

Опубликована: Окт. 24, 2023

Язык: Английский

Процитировано

122
Alzheimer's disease drug development pipeline: 2024 DOI Creative Commons
Jeffrey L. Cummings, Yadi Zhou, Garam Lee

и другие.

Alzheimer s & Dementia Translational Research & Clinical Interventions, Год журнала: 2024, Номер 10(2)

Опубликована: Апрель 1, 2024

New therapies to prevent or delay the onset of symptoms, slow progression, improve cognitive and behavioral symptoms Alzheimer's disease (AD) are needed.

Язык: Английский

Процитировано

118