Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

2020 ◽  
Vol 13 (4) ◽  
pp. 273-294 ◽  
Author(s):  
Elahe Zarini-Gakiye ◽  
Javad Amini ◽  
Nima Sanadgol ◽  
Gholamhassan Vaezi ◽  
Kazem Parivar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Small Molecules ◽  
Clinical Trial Design ◽  
Treatment Approaches ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Approved Drugs ◽  
Tau Aggregation

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

scholarly journals Some Candidate Drugs for Pharmacotherapy of Alzheimer’s Disease

2021 ◽  
Vol 14 (5) ◽  
pp. 458
Author(s):  
Barbara Miziak ◽  
Barbara Błaszczyk ◽  
Stanisław J. Czuczwar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Ischemia ◽  
Neurodegenerative Disorder ◽  
Neuropsychiatric Symptoms ◽  
Antidepressant Drugs ◽  
Cancer Drug ◽  
Novel Treatments ◽  
Close Relationship ◽  
Approved Drugs

Alzheimer’s disease (AD; progressive neurodegenerative disorder) is associated with cognitive and functional impairment with accompanying neuropsychiatric symptoms. The available pharmacological treatment is of a symptomatic nature and, as such, it does not modify the cause of AD. The currently used drugs to enhance cognition include an N-methyl-d-aspartate receptor antagonist (memantine) and cholinesterase inhibitors. The PUBMED, Medical Subject Heading and Clinical Trials databases were used for searching relevant data. Novel treatments are focused on already approved drugs for other conditions and also searching for innovative drugs encompassing investigational compounds. Among the approved drugs, we investigated, are intranasal insulin (and other antidiabetic drugs: liraglitude, pioglitazone and metformin), bexarotene (an anti-cancer drug and a retinoid X receptor agonist) or antidepressant drugs (citalopram, escitalopram, sertraline, mirtazapine). The latter, especially when combined with antipsychotics (for instance quetiapine or risperidone), were shown to reduce neuropsychiatric symptoms in AD patients. The former enhanced cognition. Procognitive effects may be also expected with dietary antioxidative and anti-inflammatory supplements—curcumin, myricetin, and resveratrol. Considering a close relationship between brain ischemia and AD, they may also reduce post-brain ischemia neurodegeneration. An investigational compound, CN-105 (a lipoprotein E agonist), has a very good profile in AD preclinical studies, and its clinical trial for postoperative dementia is starting soon.

scholarly journals Potential Therapeutic Strategies for Alzheimer’s Disease Targeting or Beyondβ-Amyloid: Insights from Clinical Trials

2014 ◽  
Vol 2014 ◽  
pp. 1-22 ◽  
Author(s):  
Qiutian Jia ◽  
Yulin Deng ◽  
Hong Qing
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Drug Targets ◽  
Neurodegenerative Disorder ◽  
Therapeutic Strategies ◽  
Therapeutic Approaches ◽  
Drug Candidates ◽  
Effective Drugs ◽  
Novel Drug

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with two hallmarks:β-amyloid plagues and neurofibrillary tangles. It is one of the most alarming illnesses to elderly people. No effective drugs and therapies have been developed, while mechanism-based explorations of therapeutic approaches have been intensively investigated. Outcomes of clinical trials suggested several pitfalls in the choice of biomarkers, development of drug candidates, and interaction of drug-targeted molecules; however, they also aroused concerns on the potential deficiency in our understanding of pathogenesis of AD, and ultimately stimulated the advent of novel drug targets tests. The anticipated increase of AD patients in next few decades makes development of better therapy an urgent issue. Here we attempt to summarize and compare putative therapeutic strategies that have completed clinical trials or are currently being tested from various perspectives to provide insights for treatments of Alzheimer’s disease.

Anti-Aβ drug candidates in clinical trials and plasmonic nanoparticle-based drug-screen for Alzheimer's disease

The Analyst ◽  
2018 ◽  
Vol 143 (10) ◽  
pp. 2204-2212 ◽  
Author(s):  
Dongtak Lee ◽  
Gyudo Lee ◽  
Dae Sung Yoon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Gold Nanoparticle ◽  
Drug Screening ◽  
Drug Screen ◽  
Plasmonic Nanoparticle ◽  
Drug Candidates

This review surveys the important developments of drug candidates for Alzheimer's disease and highlights gold nanoparticle-based anti-Aβ drug-screening.

scholarly journals Pharmacological targeting of MCL-1 promotes mitophagy and improves disease pathologies in an Alzheimer’s disease mouse model

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xufeng Cen ◽  
Yanying Chen ◽  
Xiaoyan Xu ◽  
Ronghai Wu ◽  
Fusheng He ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Therapeutic Intervention ◽  
Drug Candidates ◽  
Model Of Alzheimer’S Disease ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Shed Light

AbstractThere is increasing evidence that inducing neuronal mitophagy can be used as a therapeutic intervention for Alzheimer’s disease. Here, we screen a library of 2024 FDA-approved drugs or drug candidates, revealing UMI-77 as an unexpected mitophagy activator. UMI-77 is an established BH3-mimetic for MCL-1 and was developed to induce apoptosis in cancer cells. We found that at sub-lethal doses, UMI-77 potently induces mitophagy, independent of apoptosis. Our mechanistic studies discovered that MCL-1 is a mitophagy receptor and directly binds to LC3A. Finally, we found that UMI-77 can induce mitophagy in vivo and that it effectively reverses molecular and behavioral phenotypes in the APP/PS1 mouse model of Alzheimer’s disease. Our findings shed light on the mechanisms of mitophagy, reveal that MCL-1 is a mitophagy receptor that can be targeted to induce mitophagy, and identify MCL-1 as a drug target for therapeutic intervention in Alzheimer’s disease.

scholarly journals Protection against Amyloid-β Oligomer Neurotoxicity by Small Molecules with Antioxidative Properties: Potential for the Prevention of Alzheimer’s Disease Dementia

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 132
Author(s):  
Wataru Araki ◽  
Fuyuki Kametani
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Critical Role ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Aβ Oligomers ◽  
Antioxidative Properties ◽  
Drug Candidates ◽  
Β Protein

Soluble oligomeric assemblies of amyloid β-protein (Aβ), called Aβ oligomers (AβOs), have been recognized as primary pathogenetic factors in the molecular pathology of Alzheimer’s disease (AD). AβOs exert neurotoxicity and synaptotoxicity and play a critical role in the pathological progression of AD by aggravating oxidative and synaptic disturbances and tau abnormalities. As such, they are important therapeutic targets. From a therapeutic standpoint, it is not only important to clear AβOs or prevent their formation, it is also beneficial to reduce their neurotoxicity. In this regard, recent studies have reported that small molecules, most with antioxidative properties, show promise as therapeutic agents for reducing the neurotoxicity of AβOs. In this mini-review, we briefly review the significance of AβOs and oxidative stress in AD and summarize studies on small molecules with AβO-neurotoxicity-reducing effects. We also discuss mechanisms underlying the effects of these compounds against AβO neurotoxicity as well as their potential as drug candidates for the prevention and treatment of AD.

Fluid Biomarkers in Clinical Trials for Alzheimer’s Disease: Current and Future Application

2021 ◽  
pp. 1-14
Author(s):  
Jianwei Yang ◽  
Longfei Jia ◽  
Yan Li ◽  
Qiongqiong Qiu ◽  
Meina Quan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Future Application ◽  
Comprehensive Overview ◽  
Ongoing Research ◽  
Drug Candidates ◽  
The Many ◽  
Almost All ◽  
The Brain

Alzheimer’s disease (AD) research is entering a unique moment in which enormous information about the molecular basis of this disease is being translated into therapeutics. However, almost all drug candidates have failed in clinical trials over the past 30 years. These many trial failures have highlighted a need for the incorporation of biomarkers in clinical trials to help improve the trial design. Fluid biomarkers measured in cerebrospinal fluid and circulating blood, which can reflect the pathophysiological process in the brain, are becoming increasingly important in AD clinical trials. In this review, we first succinctly outline a panel of fluid biomarkers for neuropathological changes in AD. Then, we provide a comprehensive overview of current and future application of fluid biomarkers in clinical trials for AD. We also summarize the many challenges that have been encountered in efforts to integrate fluid biomarkers in clinical trials, and the barriers that have begun to be overcome. Ongoing research efforts in the field of fluid biomarkers will be critical to make significant progress in ultimately unveiling disease-modifying therapies in AD.

Phytotherapeutics Against Alzheimer’s Disease: Mechanism, Molecular Targets and Challenges for Drug Development

2021 ◽  
Vol 20 ◽  
Author(s):  
Gayathri S ◽  
Raghu Chandrashekar H ◽  
Fayaz S M
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Medicinal Plants ◽  
Herbal Medicines ◽  
Molecular Targets ◽  
Holistic Approach ◽  
Tinospora Cordifolia ◽  
Acorus Calamus ◽  
Approved Drugs

: Alzheimer's disease is inflating worldwide and is combatted by only a few approved drugs. At best, these drugs treat symptomatic conditions by targeting cholinesterase and N-methyl-D-aspartate receptors. Most of the clinical trials in progress are focused to develop disease-modifying agents that aim single targets. The ‘one drug-one target’ approach is failing in the case of Alzheimer’s disease due to its labyrinth etiopathogenesis. Traditional medicinal systems like ayurveda uses a holistic approach encompassing legion of medicinal plants exhibiting multimodal activity. Recent advances in high-throughput technologies have catapulted the research in the arena of ayurveda, specifically in identifying plants with potent anti-Alzheimer’s disease properties and their phytochemical characterization. Nonetheless, clinical trials of very few herbal medicines are in progress. This review is a compendium of Indian plants and ayurvedic medicines against Alzheimer’s disease and their paraphernalia. A record of 230 plants that are found in India with anti-Alzheimer’s disease potential and about 500 phytochemicals from medicinal plants has been solicited with the hope of exploring the unexplored. Further, the molecular targets of phytochemicals isolated from commonly used medicinal plants such as Acorus calamus, Bacopa monnieri, Convolvulus pluricaulis, Tinospora cordifolia and Withania somnifera have been reviewed with respect to their multidimensional property such as antioxidant, anti-inflammation, anti-aggregation, synaptic plasticity modulation, cognition and memory enhancing activity. In addition, the strengths, and challenges in ayurvedic medicine that limit its use as mainstream therapy is discussed and a framework for the development of herbal medicine has been proposed.

scholarly journals Current Trends in the Development of Drugs for the Treatment of Alzheimer’s Disease and their Clinical Trials

2018 ◽  
Vol 1 (3) ◽  
pp. e00015 ◽  
Author(s):  
S.O. Bachurin ◽  
E.V. Bovina ◽  
A.A. Ustyugov
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Neuronal Loss ◽  
Phase Iii ◽  
Molecular Pathways ◽  
Drug Candidates ◽  
Neurodegenerative Process ◽  
Thomson Reuters ◽  
Disease Modifying Agents

Intracellular and extracellular accumulation of fibrillary proteins, beta-amyloid and hyperphosphorylated Tau, in patients with Alzheimer’s disease (AD) leads to chronic and progressive neurodegenerative process. Overaccumulation of aggregates results in synaptic dysfunction and inevitable neuronal loss. Although the exact molecular pathways of the AD still require better understanding, it is clear this neuropathology is a multifactorial disorder where the advanced age is the main risk factor. Lately, several dozens of drug candidates have succeeded to phase II clinical trials; however, none has passed phase III. In this review we summarize existing data on anti-AD therapeutic agents currently undergoing clinical trials and included in the public websites www.clinicaltrials.gov and Alzforum.org as well as the Thomson Reuters «Integrity» database. We revealed three major trends in AD drug discovery. First, developing of “disease-modifying agents” could potentially slow the progression of structural and functional abnormalities in the central nervous system providing sustainable improvements of cognitive functions, which persist even after drug withdrawal. Secondly, the focused design of multitargeted drugs acting on multiple key molecular pathways. Finally, the repositioning of drugs that are already available on the market for the novel (anti-AD) application provides a promising strategy for finishing clinical trials and re-marketing.

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