The path forward in Alzheimer's disease therapeutics: Reevaluating the amyloid cascade hypothesis

Alzheimer s & Dementia, Journal Year: 2019, Volume and Issue: 16(11), P. 1553 - 1560

Published: Nov. 6, 2019

Abstract Development of disease‐modifying treatments for Alzheimer's disease (AD) has been challenging, with no drugs approved to date. The failures several amyloid‐targeted programs have led many dismiss the amyloid beta (Aβ) hypothesis AD. An antiamyloid antibody aducanumab recently showed modest but significant efficacy in a phase 3 trial, providing important validation as therapeutic target. However, inconsistent results observed may be explained by limited brain penetration and lack selectivity soluble Aβ oligomers, which are implicated upstream drivers neurodegeneration multiple studies. agents that can effectively inhibit oligomer formation or block their toxicity is therefore warranted. ideal drug would cross blood‐brain barrier efficiently achieve sustained levels continuously prevent toxicity. A late‐stage candidate these attributes ALZ‐801, an oral favorable safety profile high robustly formation. upcoming trial ALZ‐801 APOE4/4 homozygous patients early AD will test this hypothesis.

Language: Английский

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The China Alzheimer Report 2022

General Psychiatry, Journal Year: 2022, Volume and Issue: 35(1), P. e100751 - e100751

Published: Feb. 1, 2022

China's population has rapidly aged over the recent decades of social and economic development as neurodegenerative disorders have proliferated, especially Alzheimer's disease (AD) related dementias (ADRD). AD's incidence rate, morbidity, mortality steadily increased to make it presently fifth leading cause death among urban rural residents in China magnify resulting financial burdens on individuals, families society. The 'Healthy Action' plan 2019-2030 promotes transition from treatment health maintenance for this expanding with ADRD. This report describes epidemiological trends, evaluates burden disease, outlines current clinical diagnosis status delineates existing available public resources. More specifically, examines impact ADRD, including prevalence, mortality, costs, usage care, overall effect caregivers In addition, special presents technical guidance supports prevention AD, provides expertise guide relevant governmental healthcare policy suggests an information platform international exchange cooperation.

Language: Английский

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SIRT2: Controversy and multiple roles in disease and physiology

Ageing Research Reviews, Journal Year: 2019, Volume and Issue: 55, P. 100961 - 100961

Published: Sept. 7, 2019

Language: Английский

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Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer’s disease: a systematic review

Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 72, P. 101496 - 101496

Published: Oct. 22, 2021

Alzheimer's disease (AD) is the most prevalent neurodegenerative in ageing, affecting around 46 million people worldwide but few treatments are currently available. The etiology of AD still puzzling, and new drugs development clinical trials have high failure rates. Urgent outline an integral (multi-target) effective treatment needed. Accumulation amyloid-β (Aβ) peptides considered one fundamental neuropathological pillars disease, its dyshomeostasis has shown a crucial role onset. Therefore, many amyloid-targeted therapies been investigated. Here, we will systematically review recent (from 2014) investigational, follow-up studies focused on anti-amyloid strategies to summarize analyze their current potential. Combination anti-Aβ with developing early detection biomarkers other therapeutic agents acting functional changes be highlighted this review. Near-term approval seems likely for several against Aβ, FDA monoclonal oligomers antibody –aducanumab– raising hopes controversies. We conclude that, oligomer-epitope specific Aβ implementation multiple improved risk prediction methods allowing detection, together factors such as hyperexcitability AD, could key slowing global pandemic.

Language: Английский

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Blood-brain barrier opening with focused ultrasound in Parkinson’s disease dementia

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Feb. 3, 2021

Abstract MR-guided focused ultrasound (MRgFUS), in combination with intravenous microbubble administration, has been applied for focal temporary BBB opening patients neurodegenerative disorders and brain tumors. MRgFUS could become a therapeutic tool drug delivery of putative neurorestorative therapies. Treatment Parkinson’s disease dementia (PDD) is an important unmet need. We initiated prospective, single-arm, non-randomized, proof-of-concept, safety feasibility phase I clinical trial (NCT03608553), which still progress. The primary outcomes the study were to demonstrate safety, reversibility disruption PDD, targeting right parieto-occipito-temporal cortex where cortical pathology foremost this state. Changes β-amyloid burden, metabolism after treatments neuropsychological assessments, analyzed as exploratory measurements. Five recruited from October 2018 until May 2019, received two treatment sessions separated by 2–3 weeks. results are set out descriptive manner. Overall, procedure was feasible reversible no serious or radiological side effects. report junction 8/10 5 demonstrated gadolinium enhancement. In all cases procedures uneventful effects encountered associated opening. From pre- post-treatment, mild cognitive improvement observed, major changes detected amyloid fluorodeoxyglucose PET. MRgFUS-BBB PDD thus safe, reversible, can be performed repeatedly. This provides encouragement concept treat PD other disorders.

Language: Английский

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A Perspective on Multi-target Drugs for Alzheimer’s Disease

Trends in Pharmacological Sciences, Journal Year: 2020, Volume and Issue: 41(7), P. 434 - 445

Published: May 21, 2020

Language: Английский

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Adult Hippocampal Neurogenesis in Aging and Alzheimer's Disease

Stem Cell Reports, Journal Year: 2021, Volume and Issue: 16(4), P. 681 - 693

Published: Feb. 26, 2021

Cognitive deficits associated with Alzheimer's disease (AD) severely impact daily life for the millions of affected individuals. Progressive memory impairment in AD patients is degeneration hippocampus. The dentate gyrus hippocampus, a region critical learning and functions, site adult neurogenesis mammals. Recent evidence humans indicates that hippocampal likely persists throughout life, but declines age strikingly impaired AD. Our understanding how supports healthy adults only beginning to emerge. extent which decreased contributes cognitive decline aging remains poorly understood. However, studies rodent models other neurodegenerative diseases raise possibility targeting may ameliorate dysfunction Here, we review recent progress impacted context

Language: Английский

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Impact of Anti-amyloid-β Monoclonal Antibodies on the Pathology and Clinical Profile of Alzheimer’s Disease: A Focus on Aducanumab and Lecanemab

Frontiers in Aging Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: April 12, 2022

Alzheimer's disease (AD) is the most prevalent form of age-related dementia in world, and its main pathological features consist amyloid-β (Aβ) plaque deposits neurofibrillary tangles formed by hyperphosphorylated tau protein. So far, only a few AD treatments approved have been applied clinic, but effects these drugs are limited for partial symptomatic relief to patients with unable alter progression. Later, all efforts targeting pathogenic factors were unsuccessful over past decades, which suggested that pathogenesis complex. Recently, disease-modifying therapies (DMTs) can change underlying pathophysiology AD, anti-Aβ monoclonal antibodies (mabs) (e.g., aducanumab, bapineuzumab, gantenerumab, solanezumab, lecanemab) developed successively conducted clinical trials based on theory systemic failure cell-mediated Aβ clearance contributes occurrence In review, we summarized recent studies therapeutic trial results mabs AD. Specifically, focused discussion impact aducanumab lecanemab pathology profiles. The review provides possible evidence applying immunotherapy analyzes lessons learned from order further study adverse

Language: Английский

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Blood neuro‐exosomal synaptic proteins predict Alzheimer's disease at the asymptomatic stage

Alzheimer s & Dementia, Journal Year: 2020, Volume and Issue: 17(1), P. 49 - 60

Published: Aug. 10, 2020

Exosomes are an emerging candidate for biomarkers of Alzheimer's disease (AD). This study investigated whether exosomal synaptic proteins can predict AD at the asymptomatic stage.We conducted a two-stage-sectional (discovery stage: AD, 28; amnestic mild cognitive impairment [aMCI], 25; controls, 29; validation 73; aMCI, 71; 72), including preclinical (160) and controls (160), confirmation in familial (mutation carriers: 59; non-mutation 62).The concentrations growth associated protein 43 (GAP43), neurogranin, synaptosome 25 (SNAP25), synaptotagmin 1 were lower than (P < .001). Exosomal biomarker levels correlated with those cerebrospinal fluid (R2 = 0.54-0.70). The combination detected 5 to 7 years before (area under curve 0.87-0.89).This revealed that GAP43, SNAP25, act as effective prediction impairment.

Language: Английский

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Amyloid Beta in Aging and Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(21), P. 12924 - 12924

Published: Oct. 26, 2022

Alzheimer’s disease (AD), is a progressive neurodegenerative that affects behavior, thinking, learning, and memory in elderly individuals. AD occurs two forms, early onset familial late-onset sporadic; genetic mutations PS1, PS2, APP genes cause AD, combination of lifestyle, environment factors causes the sporadic form disease. However, accelerated progression noticed patients with AD. Disease-causing pathological changes are synaptic damage, mitochondrial structural functional changes, addition to increased production accumulation phosphorylated tau (p-tau), amyloid beta (Aβ) affected brain regions patients. Aβ peptide derived from precursor protein (APP) by proteolytic cleavage gamma secretases. glycoprotein plays significant role maintaining neuronal homeostasis like signaling, development, intracellular transport. reported have both protective toxic effects neurons. The purpose our article summarize recent developments its association synapses, mitochondria, microglia, astrocytes, interaction p-tau. Our also covers therapeutic strategies reduce toxicities discusses reasons for failures therapeutics.

Language: Английский

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