Alzheimer's Disease: Progress in the Development of Anti-amyloid Disease-Modifying Therapies

CNS Spectrums ◽  
2007 ◽  
Vol 12 (2) ◽  
pp. 113-123 ◽  
Author(s):  
Daniel D. Christensen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Amyloid Β ◽  
Phase Iii ◽  
Peroxisome Proliferator ◽  
Serious Adverse Events ◽  
Amyloid Disease ◽  
Aβ Aggregation ◽  
Disease Modifying

ABSTRACTThe amyloid hypothesis—the leading mechanistic theory of Alzheimer's disease—states that an imbalance in production or clearance of amyloid β (Aβ) results in accumulation of Aβ and triggers a cascade of events leading to neurodegeneration and dementia. The number of persons with Alzheimer's disease is expected to triple by mid-century. If steps are not taken to delay the onset or slow the progression of Alzheimer's disease, the economic and personal tolls will be immense. Different classes of potentially disease-modifying treatments that interrupt early pathological events (ie, decreasing production or aggregation of Aβ or increasing its clearance) and potentially prevent downstream events are in phase II or III clinical studies. These include immunotherapies; secretase inhibitors; selective Aβ42-lowering agents; statins; anti-Aβ aggregation agents; peroxisome proliferator-activated receptor-gamma agonists; and others. Safety and serious adverse events have been a concern with immunotherapy and γ-secretase inhibitors, though both continue in clinical trials. Anti-amyloid disease-modifying drugs that seem promising and have reached phase III clinical trials include those that selectively target Aβ42 production (eg, tarenflurbil), enhance the activity of α-secretase (eg, statins), and block Aβ aggregation (eg, transiposate).

scholarly journals Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

2020 ◽  
Vol 21 (16) ◽  
pp. 5858 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Md. Tanvir Kabir ◽  
Md. Sohanur Rahman ◽  
Tapan Behl ◽  
Philippe Jeandet ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Amyloid Β ◽  
Aβ Oligomers ◽  
Aβ Aggregation ◽  
Clinical Benefits

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.

scholarly journals New Approacher in the Development of Alzheimer’s Disease Modifying Drugs

2021 ◽  
pp. 88
Author(s):  
◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Tau Protein ◽  
Phase Iii ◽  
Disease Modifying Drugs ◽  
Phase Iii Clinical Trials ◽  
Research Level ◽  
Disease Modifying ◽  
Pathological Stages

Introduction: Alzheimer’s disease is a more common neurodegenerative disease, affecting 25 million people worldwide, or accounting for about 60 to 70% of all dementia cases. There is currently no exact mechanism to explain the pathophysiology of Alzheimer’s disease, however, cascading metabolic amyloid and post-translational review of tau protein are used as major hypotheses. Objective: To demonstrate in the literature new approaches in the development of Alzheimer’s disease modifiers. Methodology: For the accomplishment of this study made in the bibliographical survey of scientific literature and respect to the approached subject, in the databases PUBMED, ScienceDirect, Scielo and Scopus. Results: Alzheimer’s disease-modifying drugs are not yet available, but many patients may, however, develop phase III clinical trials and are intended to modify as pathological stages leading to the disease. As disease-modifying therapies under study, these changes also affect Aβ and tau protein and also cause inflammation and oxidative damage. The results obtained in the clinical trials performed were positive and promising and are still under study. The results show that there is still a long way to go in the development of Alzheimer’s disease modifying drugs. Conclusion: The results demonstrated that there is still a long way to go in the development of Alzheimer’s disease modifying drugs, but nevertheless levels at the research level should be continued in order to improve the pathophysiology of the disease and find an effective treatment for this disease the same.

Clinical Trials of Amyloid-Based Therapies for Alzheimer's Disease

CNS Spectrums ◽  
2007 ◽  
Vol 12 (S1) ◽  
pp. 7-10 ◽  
Author(s):  
Pierre N. Tariot
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Immunoglobulin A ◽  
Disease Process ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Amyloid Disease ◽  
Therapeutic Modalities ◽  
Disease Modifying

AbstractWe appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ42 secretion is the triggering event in the pathogenesis of Alzheimer's disease, and that tau aggregation may be an important secondary event linked to neurodegeneration. Prophylactic administration of anti-amyloid agents designed to prevent Aβ accumulation in persons with subclinical disease is likely to be more effective than therapeutic interventions in established Alzheimer's disease. Drug development programs in Alzheimer's disease focus primarily on agents with anti-amyloid disease-modifying properties, and many different pharmacologic approaches to reducing amyloid pathology and tauopathy are being studied. Classes of therapeutic modalities currently in advanced-stage clinical trial testing include forms of immunotherapy (activeβ-amyloid immunoconjugate and human intravenous immunoglobulin), a γ-secretase inhibitor, the selective Aβ42-lowering agent R-flurbiprofen, and the anti-aggregation agent tramiprosate. Non-traditional dementia therapies such as the HMG-CoA reductase inhibitors (statins), valproate, and lithium are now being assessed for clinical benefit as anti-amyloid disease-modifying treatments. Positive findings of efficacy and safety from clinical studies are necessary but not sufficient to demonstrate that a drug has disease-modifying properties. Definitive proof of disease-modification requires evidence from validated animal models of Alzheimer's disease; rigorously controlled clinical trials showing a significantly improved, stabilized, or slowed rate of decline in cognitive and global function compared to placebo; and prospectively obtained evidence from surrogate biomarkers that the treatment resulted in measurable biological changes associated with the underlying disease process.

scholarly journals Mitigating Alzheimer’s Disease with Natural Polyphenols: A Review

2019 ◽  
Vol 16 (6) ◽  
pp. 529-543 ◽  
Author(s):  
Roger Gaudreault ◽  
Normand Mousseau
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Treatment Strategies ◽  
Amyloid Β ◽  
Molecular Structures ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Root Cause ◽  
Aβ Aggregation ◽  
High Concentrations

:According to Alzheimer’s Disease International (ADI), nearly 50 million people worldwide were living with dementia in 2017, and this number is expected to triple by 2050. Despite years of research in this field, the root cause and mechanisms responsible for Alzheimer’s disease (AD) have not been fully elucidated yet. Moreover, promising preclinical results have repeatedly failed to translate into patient treatments. Until now, none of the molecules targeting AD has successfully passed the Phase III trial. Although natural molecules have been extensively studied, they normally require high concentrations to be effective; alternately, they are too large to cross the blood-brain barrier (BBB).:In this review, we report AD treatment strategies, with a virtually exclusive focus on green chemistry (natural phenolic molecules). These include therapeutic strategies for decreasing amyloid-β (Aβ) production, preventing and/or altering Aβ aggregation, and reducing oligomers cytotoxicity such as curcumin, (-)-epigallocatechin-3-gallate (EGCG), morin, resveratrol, tannic acid, and other natural green molecules. We also examine whether consideration should be given to potential candidates used outside of medicine and nutrition, through a discussion of two intermediate-sized green molecules, with very similar molecular structures and key properties, which exhibit potential in mitigating Alzheimer’s disease.

Measuring Disease Modification in Alzheimer's Disease

CNS Spectrums ◽  
2007 ◽  
Vol 12 (S1) ◽  
pp. 11-14
Author(s):  
Jeffrey L. Cummings
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immunoglobulin A ◽  
Disease Process ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Disease Modification ◽  
Amyloid Disease ◽  
Therapeutic Modalities ◽  
Disease Modifying

AbstractWe appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ42 secretion is the triggering event in the pathogenesis of Alzheimer's disease, and that tau aggregation may be an important secondary event linked to neurodegeneration. Prophylactic administration of anti-amyloid agents designed to prevent Aβ accumulation in persons with subclinical disease is likely to be more effective than therapeutic interventions in established Alzheimer's disease. Drug development programs in Alzheimer's disease focus primarily on agents with anti-amyloid disease-modifying properties, and many different pharmacologic approaches to reducing amyloid pathology and tauopathy are being studied. Classes of therapeutic modalities currently in advanced-stage clinical trial testing include forms of immunotherapy (active β -amyloid immunoconjugate and human intravenous immunoglobulin), a γ-secretase inhibitor, the selective Aβ42-lowering agent R-flurbiprofen, and the anti-aggregation agent tramiprosate. Non-traditional dementia therapies such as the HMG-CoA reductase inhibitors (statins), valproate, and lithium are now being assessed for clinical benefit as anti-amyloid disease-modifying treatments. Positive findings of efficacy and safety from clinical studies are necessary but not sufficient to demonstrate that a drug has disease-modifying properties. Definitive proof of disease-modification requires evidence from validated animal models of Alzheimer's disease; rigorously controlled clinical trials showing a significantly improved, stabilized, or slowed rate of decline in cognitive and global function compared to placebo; and prospectively obtained evidence from surrogate biomarkers that the treatment resulted in measurable biological changes associated with the underlying disease process.

scholarly journals What We Learn from the CTAD 2018 (Clinical Trials Alzheimer’s Disease)

2018 ◽  
pp. 1-2
Author(s):  
B. Vellas ◽  
P. Aisen ◽  
M. Weiner ◽  
J. Touchon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Safety Data ◽  
Phase Iii ◽  
Drug Trials ◽  
New Developments ◽  
Fda Guidance ◽  
Clinical Biomarkers ◽  
Early Alzheimer’S Disease

We are happy to publish the CTAD 2018 abstracts in the present JPAD issue. As you can see many new interesting studies are presented in this issue of the journal: from new drug trials to biomarkers, imaging studies, as well as new clinical outcomes. More specifically, we will have several hot topics presentation on: 1. Major drug trials using bace inhibitors (verubecestat, lanabecestat, atabecestat, elenbecestat…) in the early phase of the disease (APECS early trials…). Both clinical, biomarkers (MRI, CSF, PET) and safety data will be presented. 2. New data on blood biomarkers including a keynote from R. Bateman, and presentations from Araclon and Roche biomarkers. 3. Results from phase III and IIB trials including a novel and multi-targeted oligosaccharide in patients with mild-moderate AD in China; the AMBAR (Alzheimer’s Management By Albumin Replacement) study, the TOMMORROW trial: a trial to delay the onset of MCI due to AD and qualify a genetic biomarker algorithm, the 18-month STEADFAST trial of azeliragon in participants with mild Alzheimer’s Disease; a longitudinal 148-week extension 4. Results 18 from F-AV-1451-A16: a clinicopathological study of the correspondence between flortaucipir PET imaging and post-mortem assessment of tau pathology. 5. Latest developments in anti-amyloid monoclonal antibodies including aducanumab nonnegligible, and new results and data analyses of the BAN2401 study 201 in early AD. 6. New developments with safety and efficacy of lemborexant for sleep-wake regulation in patients with irregular sleep-wake rhythm disorders and Alzheimer’s Disease dementia. 7. Advances with the ABBV-8E12, a humanized anti-tau monoclonal antibody, for the treatment of early Alzheimer’s Disease. 8. Endpoints for early Alzheimer’s Disease clinical trials: interpretation and application of the draft FDA guidance. And many others… It is important to underline that a not negligible number of abstracts concern non amyloid targets (eg: Tau-related targets but also targets outside the classical AD cascade).

scholarly journals Cu-Based Turn-on Fluorescent Sensors for Cu-rich Amyloid β Aggregates

2021 ◽  
Author(s):  
Yiran Huang ◽  
Liang Sun ◽  
Liviu M. Mirica
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fluorescence Imaging ◽  
Protein Misfolding ◽  
Picolinic Acid ◽  
Amyloid Β ◽  
Fluorescent Sensors ◽  
Aβ Oligomers ◽  
Turn On ◽  
Aβ Aggregation

<div>Protein misfolding and metal dishomeostasis are two key</div><div>pathological factors of Alzheimer’s disease. Previous studies have showed that Cu‐mediated Aβ aggregation pathways lead to formation of neurotoxic Aβ oligomers. Herein, we reported a series of picolinic acid‐based Cu‐activatable sensors, which can be used for the fluorescence imaging of Cu‐rich Aβ aggregates.</div>

Alzheimer’s Disease and other Tauopathies: Exploring Efficacy of Medicinal Plant-Derived Compounds in Alleviating Tau-Mediated Neurodegeneration

2021 ◽  
Vol 14 ◽  
Author(s):  
Siva Sundara Kumar Durairajan ◽  
Karthikeyan Selvarasu ◽  
Minu Rani Bera ◽  
Kaushik Rajaram ◽  
Ashok Iyaswamy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Medicinal Plant ◽  
Tau Protein ◽  
Amyloid Β ◽  
Corticobasal Degeneration ◽  
Phase Iii ◽  
Disease Modifying Drugs ◽  
Stabilizing Agents ◽  
Phase Iii Clinical Trials

: Alzheimer’s disease (AD), a major form of dementia, has been reported to affect more than 50 million people worldwide. It is characterized by the presence of amyloid-β (Aβ) plaques and hyperphosphorylated Tau-associated neurofibrillary tangles in the brain. Apart from AD, microtubule (MT)-associated protein Tau is also involved in other neurodegenerative diseases called tauopathies, including Pick’s disease, frontotemporal lobar degeneration, progressive supranuclear palsy, and corticobasal degeneration. The recently unsuccessful phase III clinical trials related to Aβ-targeted therapeutic drugs indicated that alternative targets, such as Tau, should be studied to discover more effective and safer drugs. Recent drug discovery approaches to reduce AD-related Tau pathologies are primarily based on blocking Tau aggregation, inhibiting Tau phosphorylation, compensating impaired Tau function with MT-stabilizing agents, and targeting the degradation pathways in neuronal cells to degrade Tau protein aggregates. Owing to several limitations of the currently-available Tau-directed drugs, further studies are required to generate further effective and safer Tau-based disease-modifying drugs. Here, we review the studies that focused on medicinal plant-derived compounds capable of modulating the Tau protein, which is significantly elevated and hyperphosphorylated in AD and other tauopathies. We mainly considered the studies that focused on Tau protein as a therapeutic target. We reviewed several pertinent papers retrieved from PubMed and ScienceDirect using relevant keywords, with a primary focus on the Tau-targeting compounds from medicinal plants. These compounds include indolines, phenolics, flavonoids, coumarins, alkaloids, and iridoids, which have been scientifically proven to be Tau-targeting candidates for the treatment of AD.

Does protein aggregation drive postmitotic tissue degeneration?

2021 ◽  
Vol 13 (577) ◽  
pp. eaax0914 ◽  
Author(s):  
Jeffery W. Kelly
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Protein Aggregation ◽  
Protein Aggregate ◽  
Tissue Degeneration ◽  
Disease Modifying Therapies ◽  
Disease Modifying ◽  
Amyloid Diseases ◽  
Aggregate Structures

Pharmacological evidence, from clinical trials where patients with systemic amyloid diseases are treated with disease-modifying therapies, supports the notion that protein aggregation drives tissue degeneration in these disorders. The protein aggregate structures driving tissue pathology and the commonalities in etiology between these diseases and Alzheimer’s disease are under investigation.

REPORT FROM THE FIRST CLINICAL TRIALS ON ALZHEIMER’S DISEASE (CTAD) ASIA-CHINA 2018 : BRINGING TOGETHER GLOBAL LEADERS

2019 ◽  
pp. 1-4
Author(s):  
J.K. Chhetri ◽  
P. Chan ◽  
B. Vellas ◽  
J. Touchon ◽  
S. Gauthier
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Chinese Population ◽  
The West ◽  
Disease Modifying Therapies ◽  
Increased Risk ◽  
Disease Modifying ◽  
Past Experiences

Population of older adults in Asia, and particularly in China is increasing rapidly. Older population are at increased risk of Alzheimer’s disease (AD) and other dementias. Soon, the Chinese population with AD will represent almost half of the world’s AD population. There is a desperate need of disease modifying therapies to delay or slow the progression of AD, to tackle this emerging healthcare emergency. In this context, the first CTAD Asia-China conference was held in China to bring together Western and Asian leaders in AD. This meeting focused largely on how to develop successful trials in China, utilizing past experiences from the West.

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