scholarly journals Alzheimer's disease drug development: translational neuroscience strategies

CNS Spectrums ◽  
2013 ◽  
Vol 18 (3) ◽  
pp. 128-138 ◽  
Author(s):  
Jeffrey L. Cummings ◽  
Sarah J. Banks ◽  
Ronald K. Gary ◽  
Jefferson W. Kinney ◽  
Joseph M. Lombardo ◽  
...  
Keyword(s):  
Public Health ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Translational Research ◽  
Underlying Disease ◽  
Translational Neuroscience ◽  
New Therapies ◽  
Disease Biology ◽  
New Treatments

Alzheimer's disease (AD) is an urgent public health challenge that is rapidly approaching epidemic proportions. New therapies that defer or prevent the onset, delay the decline, or improve the symptoms are urgently needed. All phase 3 drug development programs for disease-modifying agents have failed thus far. New approaches to drug development are needed. Translational neuroscience focuses on the linkages between basic neuroscience and the development of new diagnostic and therapeutic products that will improve the lives of patients or prevent the occurrence of brain disorders. Translational neuroscience includes new preclinical models that may better predict human efficacy and safety, improved clinical trial designs and outcomes that will accelerate drug development, and the use of biomarkers to more rapidly provide information regarding the effects of drugs on the underlying disease biology. Early translational research is complemented by later stage translational approaches regarding how best to use evidence to impact clinical practice and to assess the influence of new treatments on the public health. Funding of translational research is evolving with an increased emphasis on academic and NIH involvement in drug development. Translational neuroscience provides a framework for advancing development of new therapies for AD patients.

scholarly journals Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease

GeroScience ◽  
2021 ◽  
Author(s):  
Caitlin S. Latimer ◽  
Nicole F. Liachko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Hippocampal Sclerosis ◽  
Model Organism ◽  
Amyloid Β ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Disease Biology ◽  
Rapid Cognitive Decline

AbstractAlzheimer’s disease (AD) is traditionally defined by the presence of two types of protein aggregates in the brain: amyloid plaques comprised of the protein amyloid-β (Aβ) and neurofibrillary tangles containing the protein tau. However, a large proportion (up to 57%) of AD patients also have TDP-43 aggregates present as an additional comorbid pathology. The presence of TDP-43 aggregates in AD correlates with hippocampal sclerosis, worse brain atrophy, more severe cognitive impairment, and more rapid cognitive decline. In patients with mixed Aβ, tau, and TDP-43 pathology, TDP-43 may interact with neurodegenerative processes in AD, worsening outcomes. While considerable progress has been made to characterize TDP-43 pathology in AD and late-onset dementia, there remains a critical need for mechanistic studies to understand underlying disease biology and develop therapeutic interventions. This perspectives article reviews the current understanding of these processes from autopsy cohort studies and model organism-based research, and proposes targeting neurotoxic synergies between tau and TDP-43 as a new therapeutic strategy for AD with comorbid TDP-43 pathology.

scholarly journals Drug Development in Alzheimer’s Disease—The Role of Default Mode Network Assessment in Phase II

US Neurology ◽  
2017 ◽  
Vol 13 (02) ◽  
pp. 67 ◽  
Author(s):  
Jeffrey Cummings ◽  
Kate Zhong ◽  
Dietmar Cordes ◽  
◽  
◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Phase Ii ◽  
Default Mode Network ◽  
Phase Iii ◽  
Human Cognition ◽  
Default Mode ◽  
Disease Modifying Agents ◽  
New Treatments

Alzheimer’s disease (AD) is rapidly becoming more common as the global population ages. New treatments are needed and new approaches to drug development are warranted. The phase II challenge for AD treatment development programs is how to provide proof-of-concept (POC) of the candidate agent without a large long trial equivalent to phase III. We propose that the available data support measures of the default mode network (DMN) using functional magnetic resonance imaging (fMRI) as demonstrating the effect of treatment on cognitive circuits critical to human cognition. Improved DMN function with symptomatic cognitive enhancing agents or decreased deterioration of DMN function compared to placebo in trials of disease-modifying agents would support POC and allow progression to phase III with greater confidence.

Current and Future Treatments for Alzheimer's Disease

CNS Spectrums ◽  
2009 ◽  
Vol 14 (S7) ◽  
pp. 4-7 ◽  
Author(s):  
Stephen Salloway
Keyword(s):  
Public Health ◽  
United States ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Health Problem ◽  
Public Health Problem ◽  
The United States ◽  
The World ◽  
Future Treatments ◽  
New Treatments

There are currently >5 million people in the United States who have been diagnosed with Alzheimer's disease. That prevalence rate is expected to triple as the population ages. The health and economic burden due to Alzheimer's disease is a worldwide problem, with some of the greatest burden coming from the developing world as people live longer in those societies. Throughout the world, the projected growth of Alzheimer's disease is dramatic. This is a worldwide public health problem of the highest order, and there is a compelling need to develop new treatments and methods of earlier diagnosis need to slow the progression of the disease and lessen its impact.

scholarly journals Drug Development in Alzheimer’s Disease—The Role of Default Mode Network Assessment in Phase II

2017 ◽  
Vol 13 (02) ◽  
pp. 67
Author(s):  
Jeffrey Cummings ◽  
Kate Zhong ◽  
Dietmar Cordes ◽  
◽  
◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Phase Ii ◽  
Default Mode Network ◽  
Phase Iii ◽  
Human Cognition ◽  
Default Mode ◽  
Disease Modifying Agents ◽  
New Treatments

Alzheimer’s disease (AD) is rapidly becoming more common as the global population ages. New treatments are needed and new approaches to drug development are warranted. The phase II challenge for AD treatment development programs is how to provide proof-of-concept (POC) of the candidate agent without a large long trial equivalent to phase III. We propose that the available data support measures of the default mode network (DMN) using functional magnetic resonance imaging (fMRI) as demonstrating the effect of treatment on cognitive circuits critical to human cognition. Improved DMN function with symptomatic cognitive enhancing agents or decreased deterioration of DMN function compared to placebo in trials of disease-modifying agents would support POC and allow progression to phase III with greater confidence.

Old Drugs with New Tricks; Paradigm in Drug Development Pipeline for Alzheimer’s Disease

2020 ◽  
Vol 20 ◽  
Author(s):  
Tanay Dalvi ◽  
Bhaskar Dewangan ◽  
Rudradip Das ◽  
Jyoti Rani ◽  
Suchita Dattatray Shinde ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Molecular Targets ◽  
Drug Repurposing ◽  
Phase Iii ◽  
Complex Nature ◽  
New Drug ◽  
Development Pipeline ◽  
Old Drugs

: The most common reason behind dementia is Alzheimer’s disease (AD) and it is predicted to be the third lifethreatening disease apart from stroke and cancer for the geriatric population. Till now only four drugs are available in the market for symptomatic relief. The complex nature of disease pathophysiology and lack of concrete evidences of molecular targets are the major hurdles for developing new drug to treat AD. The the rate of attrition of many advanced drugs at clinical stages, makes the de novo discovery process very expensive. Alternatively, Drug Repurposing (DR) is an attractive tool to develop drugs for AD in a less tedious and economic way. Therefore, continuous efforts are being made to develop a new drug for AD by repursing old drugs through screening and data mining. For example, the survey in the drug pipeline for Phase III clinical trials (till February 2019) which has 27 candidates, and around half of the number are drugs which have already been approved for other indications. Although in the past the drug repurposing process for AD has been reviewed in the context of disease areas, molecular targets, there is no systematic review of repurposed drugs for AD from the recent drug development pipeline (2019-2020). In this manuscript, we are reviewing the clinical candidates for AD with emphasis on their development history including molecular targets and the relevance of the target for AD.

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.

Characterization of a sensitive mouse Aβ40 PD biomarker assay for Alzheimer's disease drug development in wild-type mice

Bioanalysis ◽  
2016 ◽  
Vol 8 (10) ◽  
pp. 1067-1075 ◽  
Author(s):  
Yanmei Lu ◽  
Kwame Hoyte ◽  
William H Montgomery ◽  
Wilman Luk ◽  
Dongping He ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Wild Type

scholarly journals Frequency and Severity of Adverse Drug Reactions to Medications Prescribed for Alzheimer’s Disease in a Brazilian City: Cross-Sectional Study

2020 ◽  
Vol 11 ◽  
Author(s):  
Tânia Regina Ferreira ◽  
Luciane Cruz Lopes ◽  
Cristiane de Càssia Bergamaschi
Keyword(s):  
Public Health ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Health System ◽  
Psychiatric Disorders ◽  
Public Health System ◽  
Cross Sectional Study ◽  
Sectional Study ◽  
Drug Reactions ◽  
Cross Sectional

Background: There is lack of national studies that assess the risks associated with the drugs provided under the Brazilian public health system for treating Alzheimer’s disease. Then, this study determined the prevalence and severity of self-reported adverse drug reactions (ADRs) prescribed to patients with Alzheimer’s disease in the Brazilian public health system.Methods: A cross-sectional study was carried out based on public data from the MEDEX system (information on dispensing data, known as exceptional dispensing medications) and interviews with patients and/or caregivers who get access to Alzheimer’s drugs at a public pharmacy in a large Brazilian city, between July and September 2017, inquiring about ADRs and serious adverse events (SAEs).Results: The subjects were asked about ADRs and SAEs related to the use of donepezil, galantamine, rivastigmine and memantine. Out of 285 patients enrolled on the database, 250 participated in the study (87.7%). Among the participants, approximately 63.0% were female, 70.3% aged ≥75 years and 70.3% had comorbidities. Overall, 209 patients (83.6%) reported at least one ADR (total 1,149 ADRs) and rivastigmine was associated with the largest number of ADRs per patient (7.9 ADRs/patient). The predominant adverse effects were psychiatric disorders with common frequency (57.1%) and mild severity (89.0%). Six patients (2.4%) had SAEs that required hospitalization. The use of antipsychotics was the variable associated with ADR (OR = 4.95; 95% CI: 1.45–16.93; p = 0.011).Conclusion: There was a large number of reported ADRs and most of them were of common frequency and mild severity, being mainly related to psychiatric disorders. Considering the fragility of these patients, it is important to improve safety-related care in the use of drugs for treating this disease.

scholarly journals Brain connectivity during Alzheimer’s disease progression and its cognitive impact in a transgenic rat model

2019 ◽  
Author(s):  
Emma Muñoz-Moreno ◽  
Raúl Tudela ◽  
Xavier López-Gil ◽  
Guadalupe Soria
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Magnetic Resonance ◽  
Brain Connectivity ◽  
Brain Networks ◽  
Transgenic Animals ◽  
Brain Network ◽  
Cognitive Outcome ◽  
Structural Network ◽  
New Treatments

ABSTRACTThe research of Alzheimer’s disease (AD) in their early stages and its progression till symptomatic onset is essential to understand the pathology and investigate new treatments. Animal models provide a helpful approach to this research, since they allow for controlled follow-up during the disease evolution. In this work, transgenic TgF344-AD rats were longitudinally evaluated starting at 6 months of age. Every 3 months, cognitive abilities were assessed by a memory-related task and magnetic resonance imaging (MRI) was acquired. Structural and functional brain networks were estimated and characterized by graph metrics to identify differences between the groups in connectivity, its evolution with age, and its influence on cognition. Structural networks of transgenic animals were altered since the earliest stage. Likewise, aging significantly affected network metrics in TgF344-AD, but not in the control group. In addition, while the structural brain network influenced cognitive outcome in transgenic animals, functional network impacted how control subjects performed. TgF344-AD brain network alterations were present from very early stages, difficult to identify in clinical research. Likewise, the characterization of aging in these animals, involving structural network reorganization and its effects on cognition, opens a window to evaluate new treatments for the disease.AUTHOR SUMMARYWe have applied magnetic resonance image based connectomics to characterize TgF344-AD rats, a transgenic model of Alzheimer’s disease (AD). This represents a highly translational approach, what is essential to investigate potential treatments. TgF344-AD animals were evaluated from early to advanced ages to describe alterations in brain connectivity and how brain networks are affected by age. Results showed that aging had a bigger impact in the structural connectivity of the TgF344-AD than in control animals, and that changes in the structural network, already observed at early ages, significantly influenced cognitive outcome of transgenic animals. Alterations in connectivity were similar to the described in AD human studies, and complement them providing insights into earlier stages and a plot of AD effects throughout the whole life span.

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