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Alzheimer's disease drug-development pipeline: few candidates, frequent failures

Published on Jan 1, 2014in Alzheimer's Research & Therapy6.142
· DOI :10.1186/alzrt269
Jeffrey L. Cummings135
Estimated H-index: 135
(Cleveland Clinic),
Travis Morstorf2
Estimated H-index: 2
(Touro University Nevada),
Kate Zhong13
Estimated H-index: 13
(Cleveland Clinic)
Abstract
Introduction Alzheimer’s disease (AD) is increasing in frequency as the global population ages. Five drugs are approved for treatment of AD, including four cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA)-receptor antagonist. We have an urgent need to find new therapies for AD.
  • References (26)
  • Citations (598)
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References26
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#1Michael HayH-Index: 1
#2David W. ThomasH-Index: 2
Last. Jesse RosenthalH-Index: 1
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The most comprehensive survey of clinical success rates across the drug industry to date shows productivity may be even lower than previous estimates.
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#1Michael D. Hurd (AN: RAND Corporation)H-Index: 42
#2Paco Martorell (AN: RAND Corporation)H-Index: 12
Last. Kenneth M. LangaH-Index: 68
view all 5 authors...
Background Dementia affects a large and growing number of older adults in the United States. The monetary costs attributable to dementia are likely to be similarly large and to continue to increase. Methods In a subsample (856 persons) of the population in the Health and Retirement Study (HRS), a nationally representative longitudinal study of older adults, the diagnosis of dementia was determined with the use of a detailed in-home cognitive assessment that was 3 to 4 hours in duration and a rev...
668 CitationsSource
#1Paul S. AisenH-Index: 89
#2Bruno VellasH-Index: 97
Last. Harald HampelH-Index: 92
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A recent article in Nature Reviews Drug Discovery (Nature Rev. Drug Discov. 11, 657–660; 2012)1 highlighted the outcome of the two largest Alzheimer's disease drug development programmes to date. Results from the Phase III clinical trials of two monoclonal antibodies — bapineuzumab and solanezumab — that target amyloid-β indicated little clinical benefit of immunological attack on amyloid-β at the dementia stage of sporadic disease2 (see the 12 December 2012 press release on the Lilly website).
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3,232 CitationsSource
#1Kevin MullaneH-Index: 12
#2Michael Williams (NU: Northwestern University)H-Index: 18
Abstract The worldwide incidence of Alzheimer's disease (AD) is increasing with estimates that 115 million individuals will have AD by 2050, creating an unsustainable healthcare challenge due to a lack of effective treatment options highlighted by multiple clinical failures of agents designed to reduce the brain amyloid burden considered synonymous with the disease. The amyloid hypothesis that has been the overarching focus of AD research efforts for more than two decades has been questioned in ...
133 CitationsSource
#1Chaoyun Li (University of Tübingen)H-Index: 5
#2Azadeh Ebrahimi (University of Tübingen)H-Index: 9
Last. Hermann J. Schluesener (University of Tübingen)H-Index: 41
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Alzheimer's disease (AD) is one of the most important neurodegenerative disorders, bringing about huge medical and social burden in the elderly worldwide. Many aspects of its pathogenesis have remained unclear and no effective treatment exists for it. Within the past 20 years, various mice models harboring AD-related human mutations have been produced. These models imitate diverse AD-related pathologies and have been used for basic and therapeutic investigations in AD. In this regard, there are ...
25 CitationsSource
#1Chris Hyde (University of Exeter)H-Index: 52
#2Jaime Peters (University of Exeter)H-Index: 22
Last. Tiffany Moxham (University of Exeter)H-Index: 21
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Introduction: in 2007 the National Institute of Health and Clinical Excellence (NICE) restricted the use of acetylcholinesterase inhibitors and memantine. Methods: we conducted a health technology assessment (HTA) of the effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of AD to re-consider and up-date the evidence base used to inform the 2007 NICE decision. The systematic review of effectiveness targeted randomised controlled trials. A ...
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#1Hong-Guang Xie (Nanjing Medical University)H-Index: 1
#2Shu-Kui Wang (Nanjing Medical University)H-Index: 1
Last. Ernie Harpur (Newcastle University)H-Index: 5
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Abstract The kidney is one of the major organs drug toxicity may target. Some renal safety biomarkers have been proposed to measure kidney injury and function accordingly. Despite the widespread use for diagnosis and monitoring of renal injury and function for decades, serum creatinine and blood urea nitrogen are nonspecific biomarkers with insensitive and delayed response in the clinical setting. There is an urgent need to identify and qualify novel kidney safety biomarkers that would be used t...
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#1Jonathan J. Sabbagh (UNLV: University of Nevada, Las Vegas)H-Index: 7
#2Jefferson W. Kinney (UNLV: University of Nevada, Las Vegas)H-Index: 18
Last. Jeffrey L. Cummings (Cleveland Clinic)H-Index: 135
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Abstract Substantial resources and effort have been invested into the development of therapeutic agents for Alzheimer's disease (AD) with mixed and limited success. Research into the etiology of AD with animal models mimicking aspects of the disorder has substantially contributed to the advancement of potential therapies. Although these models have shown utility in testing novel therapeutic candidates, large variability still exists in terms of methodology and how the models are utilized. No mod...
51 CitationsSource
: Over 200 Alzheimer's disease (AD) drug candidates have failed in development, and other neuropsychiatric trials have had their validity compromised. Studies suggest that methodological errors can be a source for these compromises and failures. We gained access to documentation for phenserine, an experimental AD drug that reached phase III clinical trials. The 06 Phase III trial was cited by the developers as grounds for their abandonment of the development. We compared evidence for interventio...
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#1Xinbei Jiang (NU: Northeastern University)
#2Tianhan Gao (NU: Northeastern University)H-Index: 1
Last. Tianhan Gao (NU: Northeastern University)
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The increase in the number of patients with Alzheimer’s disease has placed a heavy burden on society and has become a major problem in the medical field. In recent years, brain-computer interface (BCI) has become an important way to explore the utilization of modern technology to improve Alzheimer’s disease. However, traditional pattern recognition methods suffer from poor classification and feature extraction. This paper proposes an end-to-end Electroencephalograph (EEG) emotion classification ...
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Alzheimer's disease (AD) and AD-related dementias (ADRD) are a class of neurodegenerative diseases affecting about 5.7 million Americans. There is no cure for AD/ADRD. Current interventions have modest effects and focus on attenuating cognitive impairment. Detection of patients at high risk of AD/ADRD is crucial for timely interventions to modify risk factors and primarily prevent cognitive decline and dementia, and thus to enhance the quality of life and reduce health care costs. This study see...
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#1Stacey J. Sukoff Rizzo (University of Pittsburgh)H-Index: 1
#2Andi Masters (IU: Indiana University)
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Introduction Preclinical testing in animal models is a critical component of the drug discovery and development process. While hundreds of interventions have demonstrated preclinical efficacy for ameliorating cognitive impairments in animal models, none have confirmed efficacy in Alzheimer's disease (AD) clinical trials. Critically this lack of translation to the clinic points in part to issues with the animal models, the preclinical assays used, and lack of scientific rigor and reproducibility ...
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#2Qiong Jiang (STU: Shantou University)H-Index: 6
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Abstract Alzheimer’s disease (AD) is characterized by deposition of β-amyloid protein (Aβ), neurofibrillary tangles and cognitive deficits resulting from neuronal cell death. In search for the molecular underpinnings of the disease, we were interested in the relationship between Aβ, L1 cell adhesion molecule and protein kinase D1 (PKD1), which are not only implicated in neural development and functional maintenance in the adult, but are also neuroprotective under pathological conditions. Based o...
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#1Kenneth L Chiou (UW: University of Washington)H-Index: 6
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Research in the basic biology of ageing is increasingly identifying mechanisms and modifiers of ageing in short-lived organisms such as worms and mice. The ultimate goal of such work is to improve human health, particularly in the growing segment of the population surviving into old age. Thus far, few interventions have robustly transcended species boundaries in the laboratory, suggesting that changes in approach are needed to avoid costly failures in translational human research. In this review...
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#1Heather J. Buchanan (Aberd.: University of Aberdeen)H-Index: 2
#2Murray Mackay (Aberd.: University of Aberdeen)
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The complex multifactorial nature of AD pathogenesis has been highlighted by evidence implicating additional neurodegenerative mechanisms, beyond that of amyloid-β (Aβ) and tau. To provide insight into cause and effect, we here investigated the temporal profile and associations of pathological changes in synaptic, endoplasmic reticulum (ER) stress and neuro-inflammatory markers. Quantifications were established via immunoblot and immunohistochemistry protocols in post-mortem lateral temporal cor...
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An overview of the impact of dementia that focuses on underdeveloped countries across the globe, and migrant and minority ethnic communities within the developed world. Increased longevity increases the risk of dementia and brings new challenges in terms of cultural perspectives and cultural obligations in the care of elders. The chapter examines these challenges in detail and their consequences in planning for support and care.
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#1Fang Yu (UMN: University of Minnesota)H-Index: 16
#2Dereck L Salisbury (UMN: University of Minnesota)H-Index: 3
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Abstract Background Despite the strong evidence of aerobic exercise as a disease-modifying treatment for Alzheimer's disease (AD) in animal models, its effects on cognition are inconsistent in human studies. A major contributor to these findings is inter-individual differences in the responses to aerobic exercise, which was well documented in the general populations but not in AD. The purpose of this study was to examine inter-individual differences in aerobic fitness and cognitive responses to ...
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INTRODUCTION: This work aims to characterize the sequence in which cognitive deficits appear in two dementia syndromes. METHODS: Event-based modeling estimated fine-grained sequences of cognitive decline in clinically-diagnosed posterior cortical atrophy (PCA) ( n = 94 ) and typical Alzheimer's disease (tAD) ( n = 61 ) at the UCL Dementia Research Centre. Our neuropsychological battery assessed memory, vision, arithmetic, and general cognition. We adapted the event-based model to handle highly n...
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#1Jin-Hui Zhou (CCDC: Chinese Center for Disease Control and Prevention)H-Index: 1
#2Yue-Bin Lv (CCDC: Chinese Center for Disease Control and Prevention)H-Index: 6
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Abstract Objective Although some people with mild cognitive impairment may not suffer from dementia lifelong, about 5% of them will progress to dementia within 1 year in community settings. However, a general tool for predicting the risk of cognitive impairment was not adequately studied among older adults. Design Prospective cohort study. Setting Community-living, older adults from 22 provinces in China. Participants We included 10,066 older adults aged 65 years and above (mean age, 83.2 ± 11.1...
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