Immunotherapy with Anti-Aβ Monoclonal Antibodies in Alzheimer’s Disease: A Critical Review on the Molecules in the Pipelines with Regulatory Considerations
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Author: Chrystelle Mavoungou and Katharina Schindowski Zimmerman
Alzheimer’s disease (AD) is the most common dementia in the industrialized world with prevalence rates far over 30% in the over 80 years old population. The dementia causes enormous cost to the social health care systems besides the personal tragedies for the patients, families and caregivers.
One of the pathological protein aggregations that occur in AD is the Amyloid-beta (Aβ) aggregation in extracellular plaques, accompanied by Tau hyperphosphorylation, chronic neuroinflammation and oxidative stress, leading to severe neurodegeneration of brain areas involved in learning and memory. Plaques, thus Aβ, appeared to be the more druggable and promising target for disease-modifying therapeutic strategies like passive immunotherapy with monoclonal antibodies (mAbs) against Aβ, though today it is clear that Aβ is a dreadful target. Meanwhile, the first-in-class mAb Bapineuzumab and the fast-follower mAb Solanezumab failed in Phase III whereas several other candidates – some of them modified 2nd generation mAbs – now entered Phase I (PF-05236812, BAN2401, SAR228810 and BIIB037) and Phase II (Gantenerumab and Crenezumab) respectively. Others are known to be in preclinical stages. On the first view, the above-cited mAbs cleared or improved amyloid burden and validated the proposed Aβ read-out biomarkers, but have yet not shown relevant improvement in the major aim in AD therapy: cognition. Also, currently under Phase III investigation, are human IgG from healthy donors. The latest, so-called IVIG, are nowadays interestingly reported to stabilize cognition in AD patients.
In this review we discuss the immunological basis for the mechanism of action of passive Aβ immunotherapy, anti-Aβ mAbs and scaffolds in the pipelines and patents, their preclinical and clinical outcome and strategies for 2nd generation biobetters.
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Author: John W. Wright and Joseph W. Harding
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The loss of neurons and synapses resulting in neurotransmitter dysfunction, along with β-amyloid peptide (Aβ) aggregation and neurofribrillary tangles, have served as the hallmarks of Alzheimer’s disease (AD). Alterations associated with neurochemical disturbances of several neurotransmitter systems appear to be the major underling cause of the cognitive and neuropsychiatric symptoms accompanying this disease. Treatments designed to target cholinergic deficiencies have provided only minimal benefit to the large majority of AD patients. As populations live longer there is a persistent and growing need for the development of new and much more efficacious treatment strategies designed to prevent progressive synaptic and neuron losses and encourage neurogenesis and synaptogenesis. There is also the emerging realization that neurodegenerative diseases such as AD, Parkinson’s disease, and Amyotrophic Lateral Sclerosis are the result of multiple insults, not one or two, and must be countered with multi-target lead compounds. The development of these new drugs requires a reevaluation of high throughput screens against protein targets in favor of the development of multi-target-directed ligands (MTDL) consisting of a single or hybrid compound capable of influencing several targets and/or systems. The present chapter focuses on this MTDL approach in the development of drugs to treat AD, but recognizes that this drug design strategy is applicable to other clinically significant diseases. This new approach represents a transition away from the “one molecule one target” high throughput screening assays, toward the rational design of drugs. As such it ushers in a new approach to drug development.
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Author: Rosaria A. Cavallaro and Andrea Fuso
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Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder characterized by severe and progressive cognitive impairment, including impaired decision making and orientation, inability to perform activities of daily living, language impairment and psycho-behavioural disturbances.
Molecular studies based on interdisciplinary approaches, including biochemical investigations, immunohistochemistry, molecular and cell biology, genetic approaches and animal models, have revealed that AD is a multifactorial disease with many different etiopathogenic mechanisms. The two major AD hallmarks are extracellular amyloid beta (A) plaques and intracellular neurofibrillary tangles (NFTs), but additional pathogenic mechanisms have been described, including inflammation, oxidative damage, iron dysregulation, cholesterol metabolism and other amyloid-independent hypotheses.
There are still no effective treatments to prevent, stop or revert AD: the existing treatments only provide symptomatic relief, but poorly affect the progression of the disease.
Current approved therapy is based on the cholinesterase inhibitors and NMDA receptor antagonists. These treatments are symptomatic and drug discovery has been directed, in recent years, to develop “disease modifying drugs” able to counteract the progression of AD by modifying the evolution of disease. Recent advances on diagnostic criteria for the disease based on biological markers, even in a preclinical phase, can facilitate the identification of new effective therapies, impacting on drug development and monitoring disease progression during therapeutic trials.
The aim of this work is to provide an overview on the main therapeutic approaches, summarizing current treatments and new molecules still under clinical development and also discussing new perspectives on therapeutic intervention.
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Author: Yasumasa Yoshiyama
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The rapid increase in size of the elderly population has resulted in a dramatic increase in the number of Alzheimer’s disease (AD) patients. To improve patients’ quality of life and reduce the economic and care burdens, the development of disease-modifying therapies directly related to the pathomechanism of AD is urgently needed. Based on the amyloid hypothesis, decreasing accumulation of Aβ in the brain is supposed to control downstream AD pathogenesis including formation of neurofibrillary tangles (NFTs) and neurodegeneration. However, the results of recent clinical trials in symptomatic AD patients aimed at Aβ removal, suppression of Aβ production or inhibition of Aβ aggregation have failed to demonstrate significant clinical efficacy. Moreover, active immunization with Aβ did not inhibit NFT formation, neurodegeneration or cognitive decline in AD patients even though it reduced Aβ burden in the brain. This suggests that Aβ-targeting therapies could not suppress tau-mediated neurodegeneration and it might autonomously progress, once it has been initiated. Therefore, the development of tau-directed therapies is an important and urgent issue for AD and related tauopathies. This chapter summarizes recent research progress in tau-directed therapies.
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Author: Zaciragic Asija
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Alzheimer's disease (AD) is a progressive and most common form of dementia. Pathogenesis of AD is multifactorial and yet fully unknown. Proper and on-time diagnosis of this disease is pivotal but however not easy to achieve. Studies indicate that early diagnosis of AD provides best treatment outcomes. Risks for AD include age, genetic, environmental, vascular, life-style factors and low educational income. Novel findings suggest that inflammation, oxidative stress as well as disturbance of immune system may also play significant role in the development of AD. This disease is neuropathologically characterized by presence of neurofibrillary tangles and senile neuritic plaques, amyloid-β peptid deposits and widespread neuronal loss. Main symptoms of AD are cognitive decline, memory loss, altered behavior and language deficit. As they progress in time, these symptoms lead to severe impairment in daily functioning and in later stages AD patients require total care. The aim of this review is to provide a comprehensive insight into the different, currently available, approaches in the treatment of AD. Furthermore, review presents findings of ongoing clinical trials and drug research studies in advanced stages of development and their application in the prevention and treatment of AD.
Based on currently available FDA guidelines, treatment options for AD include acetycholine esterase inhibitors for mild to moderate cases and memantine, an N-methyl-D-aspartate receptor antagonist, for moderate to severe forms of AD. Alongside with symptomatic drugs, novel disease modifying approaches are currently tested such as amyloid-based therapies, inhibitor and/or modulators of secretases, statins, inhibitors of receptors for advanced glycation end products, aggregation inhibitors, erythropoetin derivatives, peroxisome proliferator-activated receptor-gamma agonists and immunotherapy. Furthermore, therapeutic targets in the treatment of AD include approaches directed against tau protein such as tau protein aggregation inhibitors and inhibitors of tau kinases. Anti-inflammatory drugs and antioxidants are also used as neuroprotective advancements in AD therapy. Finally, alteration of ion homeostasis and neuronal regeneration approaches are currently implemented in the attempt to modify AD progression, stop neurodegeneration or enhance neurogenesis.
Even though AD treatment options as stated above are numerous,in majority of cases these drugs produce only modest improvements of AD symptoms and none of the available treatment options can cure or stop disease progression. Only full and complete knowledge of its etiology will provide favorable results in AD prevention and therapy.
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Author: Angela Clifford, Jennifer Stock, Stephan Bandelow, Tri Budi Rahardjo and Eef Hogervorst
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Dementia is a global problem and in this chapter we investigate modifiable protective and risk factors for dementia. The main question is when to intervene with preventative measures and which focus points should have priority to direct public health policies. Risk factors for vascular disease are also risk factors for dementia and should probably be addressed in midlife at the latest. We review evidence for the most optimal time of intervention for prevention of dementia when discussing protective and risk factors, with a focus on physical activity and cardiovascular risk factors. We also discuss other factors that may influence the relationship between physical activity and cognitive functioning and the implications for theory and practice.
Neurogenic Molecules Modulating Cell Survival Pathways, Amyloid Beta, Tau Proteins, and Metal Dyshomeostasis: An Alternative Hope for Alzheimer’s Therapy
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Author: Hailin Zheng, Mati Fridkin and Moussa B.H. Youdim
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Compelling evidence indicates that Alzheimer’s disease (AD) has multiple causes, and its effective treatment should fully address the multi factor nature of the disease. Accordingly, to achieve better efficacy, recent drug development for AD therapy has been moving from single-targeting to multi-targeting, drugs which simultaneously modulates several key disease-related/pathways. In this chapter, we explore some examples of neurogenic molecules which can reduce amyloid beta (Aβ) production, prevent oxidative stress and tau hyperphosphorylation, restore metal dyshomeostasis and also possess neuroprotective/neurorestorative effects. We also discuss the diverse mechanisms contributing to the biological activities of these neurogenic molecules, including regulation of Aβ processing and tau phosphorylation; activation of protein kinase signaling pathways; and modulation of cell survival genes and proteins.
Cognitive Decline and Alzheimer's Disease: A Central Role for Hypoxia-Obstructive Sleep Apnea and Related Stigmata in Elderly
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Author: Mak Adam Daulatzai
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Late onset Alzheimer's disease (AD) is the most common cause of dementia in the western world. Available extensive evidence supports the concept that AD is fundamentally a multifactorial syndrome that results in progressive psychiatric and cognitive impairment. Several clinico-pathological and epidemiological data emphasize overlaps of pathological cascades, e.g. aging, cerebrovascular pathology and obesity, and their synergistic effects in promoting cognitive and memory decline/AD. In comparison with normal controls, patients with amnestic mild cognitive impairment (MCI) who converted to AD showed cerebral hypoperfusion particularly in the parietal, parahippocampal, inferior temporal and fusiform gyri, whereas those who did not convert yet showed hypoperfusion in the retrosplenial cortex. This suggests that promotion and progression of cognitive decline may precede neuronal damage. The current chapter addresses this important issue and delineates the factors responsible for hypoxia, hypoxemia, cerebral hypoperfusion and compromised blood supply, brain hypometabolism in aging and AD. In the normally aged brain -perfusion, oxygen consumption and glucose metabolism remain quite unchanged from the 3rd to the 7th decade. Thereafter, they decline and lead to relatively lower hypoperfusion, and glucose hypometabolism in aging. This disturbance arises due to snoring and obstructive sleep apnea (OSA) that cause chronic intermittent hypoxia (which is highly prevalent in the obese). OSA could be as much as 50 per hour (or more) – i.e. an apnea-hypopnea index of 50. Hence a scenario of chronic hypoxia/hypoxemia may promote cerebral ischemia, changes in oxygen consumption, and glucose hypometabolism -documented in the temporo-parietal cortex of OSA sufferers as well as AD patients. A convergence of “Age” – a proinflammatory state, and several other stigmata due to hypoxia/hypoxemia may upregulate neuroinflammation and enhance oxidative stress. The confluence of the above pathogenic cascades may depress neuronal function by rendering synapses, neurotransmission, and brain metabolism dysfunctional, and thus provoke and enhance cognition impairment. This progressive/evolving neurodegenerative process is also manifested by amyloid angiopathy, and the formation/deposition of amyloid plaques and neurofibrillary tangles -the quintessential hallmarks of Alzheimer’s dementia. Animal models of intermittent hypoxia have consistently documented upregulation of amyloid beta and neuronal apoptosis -being widespread in key foci of cortex and brainstem.
Page: 315-366 (52)
Author: Chuang Wang, Rui Wang, James M. O’Donnell and Ying Xu
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Alzheimer’s disease (AD) is a most prevalent neurodegenerative disorder and most common cause of dementia, which affects approximately 36 million people worldwide as of 2011 and threatens to be the scourge of the 21st century. AD is characterized by progressive cognitive decline that usually starts with memory deficit and progresses to cause a more generalized cognitive dysfunction, behavioral dysregulation, and neuropsychiatric symptoms, which result in complete loss of life skills and death. The high morbidity and mortality are always the case attributed to lack of effective therapies and prevention strategies because many aspects of its pathogenesis remain unclear. This review discusses the effectiveness and problems with current pharmaceutical treatment. It exemplifies natural compounds and target synthetic drugs as appropriate therapies and formulates rational guidelines for prevention of AD.
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Author: Kurt A. Jellinger
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Dementia is a major public health problem that threatens to become the scourge of the 21st century. It is caused by dysfunction/loss of synapses and neurons inducing default neuronal networks. Consensus criteria for the diagnosis of the major dementia disorders have recently been updated. Clinical diagnostic accuracy using revised criteria and new biomarkers ranges from 65 to 96% (for Alzheimer disease), with a sensitivity vs. other dementias of 71 to 87% and specificity of 44 to 71%. Morphological assessment, using modern molecular biological and genetic methods, and based on homogeneous definitions, harmonized inter-laboratory techniques and assessment standards, can achieve a diagnosis/classification in almost 99%, without, however, clarifying the etiology of most of these disorders. The new National Institute on Aging-Alzheimer Association (ABC) guidelines for the pathological diagnosis of Alzheimer disease combine β-amyloid plaque phases, Braak neurofibrillary and neuritic plaque scores, also considering other pathologies. Major difficulties arise from recent separation of distinct clinico-pathological subtypes (tangle- and plaque intensive, tangle predominant, limbic-predominant and -sparing) from classical Alzheimer disease. Revised research criteria are available for dementia with Lewy bodies, Parkinson disease-dementia, frontotemporal lobe degeneration, vascular cognitive impairment, prion diseases, and other neurodegenerative dementias. However, due to considerable overlap between various neurodegenerative proteinopathies and cases with mixed pathologies, human postmortem studies entail numerous biases that affect both their general applicability and the validity of correlations. Although most neurodegenerative dementias are incurable at present, concerted prospective clinico-pathological studies using validated protocols and data fusion are warranted to overcome the limitations of the current diagnostic framework as a basis for efficient new therapy options.
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Author: Guido Crisponi, Valeria M. Nurchi, Daniela Fanni, Clara Gerosa, Sonia Nemolato, Miriam Crespo-Alonso, Leonardo Toso, Joanna I. Lachowicz and Gavino Faa
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Despite the large availability of data regarding the mechanisms at the basis of β- amyloid production in Alzheimer’s disease (AD), the factors responsible for β-amyloid accumulation in neurons of AD patients until now have not been entirely clarified. Several metal ions have been indicated as possible triggers of the main conformational modifications of β-amyloid protein, and metal homeostasis disarrangement has been proposed as a relevant pathological cofactor of neurodegeneration. Epidemiological evidences suggest a possible association between exposure to increased amounts of multiple metals and onset and progression of AD. According to this hypothesis, metals could induce oxidative stress in neurons, developing neurodegenerative disease. In this chapter, the role of various trace metals as cofactors of a poor cognitive function and of an increased risk of dementia leading to AD will be discussed. In particular, this study is aimed to critically analyze the role played by copper, iron, zinc and aluminium in neurodegeneration. Based on the current evidences concerning the relationship between these metal ions and onset and progression of AD, no definitive recommendations are, at the best of our knowledge, possible. However, foods rich in metals such as iron and copper should be discouraged, as well as caution should be suggested in exposure to aluminium sources. Further studies on the relationship between metal overexposure and AD development hopefully will open new opportunities for the prevention and management of neurodegenerative diseases.
Frontiers in Clinical Drug Research - Alzheimer Disorders is an e-Book series concerned with Alzheimer's disease (AD) that causes dementia, or loss of brain function. The disease affects the parts of the brain that deal with memory, thought, and language. Chapters in each volume focus on (Alzheimer Disorders) drug research with special emphasis on clinical trials, research on drugs in advanced stages of development and cure for Alzheimer’s disease and related disorders. Frontiers in Clinical Drug Research - Alzheimer Disorders will be of particular interest to readers interested in drug therapy this specific neurodegenerative condition and related brain disorders as the series provides relevant reviews written by experts in field of Alzheimers Disease research.