Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission

The Lancet, Journal Year: 2024, Volume and Issue: 404(10452), P. 572 - 628

Published: July 31, 2024

Language: Английский

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

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 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.

Language: Английский

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Alzheimer Disease as a Clinical-Biological Construct—An International Working Group Recommendation

JAMA Neurology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Importance Since 2018, a movement has emerged to define Alzheimer disease (AD) as purely biological entity based on biomarker findings. The recent revision of the Association (AA) criteria for AD furthers this direction. However, concerns about definition being applied clinically, understanding by society at large, and translation blood-based biomarkers into clinical practice prompt these International Working Group (IWG) updated recommendations. Objective To consider revised AA offer an alternative definitional view clinical-biological construct use. recommendations 2021 IWG diagnostic are further elaborating at-risk presymptomatic states. Evidence Review PubMed was searched articles published between July 1, 2020, March 2024, using terms “biomarker” OR “amyloid” “tau” “neurodegeneration” “preclinical” “CSF” “PET” “plasma” AND “Alzheimer’s disease.” references relevant were also searched. Findings In new criteria, can be defined clinically encompassing cognitively normal people having core 1 biomarker. literature shows that majority biomarker-positive individuals will not become symptomatic along proximate timeline. setting, disclosing diagnosis with only represents most problematic implication disease. Conclusions Relevance ultimate aim field foster effective treatments, including preventing symptoms dementia. approach diagnosing without would unwarranted potentially concerning clear knowledge when or whether ever develop. It is recommended those who amyloid-positive and, more generally, individuals, should labeled AD. Rather, they considered risk expansion viewed better specific pattern biomarkers, indicating expression in near future.

Language: Английский

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

Translational Neurodegeneration, Journal Year: 2025, Volume and Issue: 14(1)

Published: Jan. 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

Language: Английский

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Shattering the Amyloid Illusion: The Microbial Enigma of Alzheimer’s Disease Pathogenesis—From Gut Microbiota and Viruses to Brain Biofilms

Microorganisms, Journal Year: 2025, Volume and Issue: 13(1), P. 90 - 90

Published: Jan. 5, 2025

For decades, Alzheimer's Disease (AD) research has focused on the amyloid cascade hypothesis, which identifies amyloid-beta (Aβ) as primary driver of disease. However, consistent failure Aβ-targeted therapies to demonstrate efficacy, coupled with significant safety concerns, underscores need rethink our approach AD treatment. Emerging evidence points microbial infections environmental factors in pathoetiology. Although a definitive causal link remains unestablished, collective is compelling. This review explores unconventional perspectives and emerging paradigms regarding involvement pathogenesis, emphasizing gut-brain axis, brain biofilms, oral microbiome, viral infections. Transgenic mouse models show that gut microbiota dysregulation precedes Aβ accumulation, signaling pathways. Viral like Herpes Simplex Virus Type 1 (HSV-1) Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) may lead by modulating host processes immune system. peptide's antimicrobial function response infection might inadvertently promote AD. We discuss potential microbiome-based promising strategies for managing potentially preventing progression. Fecal transplantation (FMT) restores balance, reduces improves cognition preclinical models. Probiotics prebiotics reduce neuroinflammation plaques, while antiviral targeting HSV-1 vaccines shingles vaccine mitigate pathology. Developing effective treatments requires standardized methods identify measure patients, enabling personalized address individual contributions pathogenesis. Further needed clarify interactions between microbes Aβ, explore bacterial interplay, understand their broader effects translate these insights into clinical interventions.

Language: Английский

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Crossing the blood–brain barrier: emerging therapeutic strategies for neurological disease

The Lancet Neurology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Amyloid-Related Imaging Abnormalities With Donanemab in Early Symptomatic Alzheimer Disease

JAMA Neurology, Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

Importance Amyloid-related imaging abnormalities (ARIA) are the major adverse event associated with amyloid-targeting immunotherapy. Identifying clinical features and individual risk factors for ARIA could facilitate effective prediction prevention strategies. Objective To characterize in participants treated donanemab. Design, Setting, Participants These prespecified post hoc exploratory analyses use data from placebo-controlled portions of TRAILBLAZER-ALZ ALZ 2 randomized trials, conducted December 2017 to 2020 June April 2023, respectively. Additional included a stand-alone open-label addendum August 2021 through 2023. trials aged 60 85 years early symptomatic Alzheimer disease elevated amyloid levels were included. The but not addendum, had tau inclusion criteria. Interventions Placebo-controlled trial 1:1 receive placebo or donanemab, all received Donanemab was administered every 4 weeks up 72 weeks. Main Outcomes Measures primary outcomes frequency, radiographic severity, seriousness, symptoms, timing relative donanemab treatment, ARIA. Results Across 3030 total (placebo-controlled trials: 999 participants, 984 participants; addendum: 1047 participants), mean (SD) age approximately 73.7 (6.0) 1684 (55.6%) female. Frequencies ARIA–edema/effusions (ARIA-E) ARIA–microhemorrhages hemosiderin deposition (ARIA-H) higher (24.4% 31.3% respectively; 19.8% 27.2% respectively) than (1.9% 13.0%, respectively). ARIA-E mostly mild moderate severity. Serious reported 1.5% 5.8% donanemab-treated trials. Symptoms most frequently headache confusional state. In 58.3% ARIA-E, first occurred by third infusion (approximately month 3). Risk analysis demonstrated independent associations between 6 baseline variables, including increased APOE ε4 allele number, greater number microhemorrhages, presence cortical superficial siderosis, plaque, arterial pressure, decreased antihypertensive use. Conclusions Relevance is an treatment that requires safety monitoring. Individual can be assessed status findings. Trial Registrations ClinicalTrials.gov Identifiers: NCT03367403 NCT04437511

Language: 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, Journal Year: 2025, Volume and Issue: unknown, P. e00570 - e00570

Published: March 1, 2025

Language: Английский

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Amyloid-beta antibody binding to cerebral amyloid angiopathy fibrils and risk for amyloid-related imaging abnormalities

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: May 13, 2024

Abstract Therapeutic antibodies have been developed to target amyloid-beta (Aβ), and some of these slow the progression Alzheimer’s disease (AD). However, they can also cause adverse events known as amyloid-related imaging abnormalities with edema (ARIA-E). We investigated therapeutic Aβ antibody binding cerebral amyloid angiopathy (CAA) fibrils isolated from human leptomeningeal tissue study whether this related ARIA-E frequencies previously reported by clinical trials. The CAA was evaluated in vitro using immunoprecipitation, surface plasmon resonance, direct assay. Marked differences were observed. Solanezumab crenezumab showed negligible fibril no cases. Lecanemab a low fibrils, consistent its relatively frequency 12.6%, while aducanumab, bapineuzumab, gantenerumab all higher substantially (25–35%). An 24% for donanemab, correlated amount pyroglutamate-modified present. findings support proposal that antibody-CAA interactions may relate observed patients treated Aβ-based immunotherapies.

Language: Английский

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Brain volume change following anti-amyloid β immunotherapy for Alzheimer's disease: amyloid-removal-related pseudo-atrophy

The Lancet Neurology, Journal Year: 2024, Volume and Issue: 23(10), P. 1025 - 1034

Published: Sept. 19, 2024

Language: Английский

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