Frontiers in Clinical Drug Research - Alzheimer Disorders: Volume 7

Atta-ur-Rahman

• Publisher: Bentham Science Publishers
• Year: 2018
• ISBN:
  9781681085609
• Topic: Physical Sciences
• Subtopic: Clinical Chemistry

Frontiers in Clinical Drug Research - Alzheimer Disorders is a book series concerned with Alzheimer's disease AD, a disease that causes dementia, or loss of brain function. This disease affects parts of the brain that affect memory, thought, and languag

Recent Advances in Alzheimer's Drug Discovery Research

Xin-An Liu^{1, 6, *}, Brati Das², Youjun Chen³, Zuxin Chen⁴, Yosef Avchalumov¹, Xu Tian⁵, Sathyanarayanan V. Puthanveettil^{1, *}

¹ Department of Neuroscience, The Scripps Research Institute, Jupiter, FL33458, USA

² Department of Neuroscience, UConn Health, 263 Farmington Avenue, Farmington, CT 06030-3401, USA

³ Department of Neurology, School of Medicine, University of North Carolina at Chapel Hill, NC 27599, USA

⁴ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574, USA

⁵ Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina at Chapel Hill, NC 27599, USA

⁶ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, NewYork, NY 10029-6574, USA

Abstract

Alzheimer’s disease (AD) is the most common cause of age-related dementia, a deleterious neurodegenerative disorder that impairs memory, where neuropathological changes develop gradually over years to affect cognitive functions. AD is one of the most important health-care problems with over 20 million people suffering worldwide and has become a critical issue to human health, especially in aging societies. Current treatments do not prevent, stop, or delay disease progression, despite the considerable advances in knowledge of the pathogenesis of AD and in medicinal chemistry over the past quarter of a century. The neuropathologic hallmarks of AD are extracellular senile plaques of aggregated β-amyloid and intracellular neurofibrillary tangles, mainly containing the hyperphosphorylated microtubule-associated protein tau. Additional changes that may also occur in the brains of AD patients include age-related brain atrophy, synaptic pathology, and neuron loss, which contribute to cognitive impairment. So far, only four cholinesterase inhibitors and memantine have been marketed as the therapeutic strategies for Alzheimer’s disease. Despite advancements in prevention strategies, potential targets, effective biomarkers, clinical development methods, and the evaluation of potential treatments in clinical trials. This chapter summarizes our best understanding of the etiology, animal models

currently under study, pharmacotherapeutic targets, and molecular pathways that curtail the progression of AD. This knowledge will help to strategize the development and clinical use of any new drugs for AD therapy in future.

Keywords: Alzheimer’s Disease, Drug Development, Pharmacotherapeutic Targets, Transgenic Models.

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^* Corresponding authors, Xin-An Liu: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, NewYork, NY 10029-6574, USA; Tel: [phone]; E-mail: [email protected]; Sathyanarayanan V. Puthanveettil: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA; Tel: [phone]; Fax: [phone]; E-mail: [email protected]

INTRODUCTION

The Prevalence of Alzheimer’s Disease from Epidemiological Studies and Public Health Impact

Alzheimer's disease is a fatal, progressive, degenerative brain disease that slowly destroys memory and thinking skills, often starting 5, 10 or even 20 years before symptoms appear. It is also the most common form of dementia worldwide and the top cause for disabilities in later life. According to 2017 Alzheimer’s Statistics, nearly 44 million people have Alzheimer’s or a related dementia around the world and an estimated 5.5 million Americans of all ages have Alzheimer's disease, in another words, one in 10 people age 65 and older (10 percent) has Alzheimer's dementia (Latest Facts & Figures Report from Alzheimer's Association). Alzheimer is most common in Western Europe and least prevalent in Sub-Saharan Africa (Alzheimer’s Disease International).

Of the 5.5 million Americans with Alzheimer's in 2017, an estimated 5.3 million are age 65 and older and approximately 200,000 individuals are under age 65 and have younger-onset Alzheimer's (early onset Alzheimer's) (Data from 2017 Alzheimer’s Disease facts and figures at alz.org). Further, AD is the sixth-leading cause of death in the United States and the fifth-leading cause of death among those aged 65 and older. Alzheimer’s care has become an overwhelming burden for society and families as the global cost of Alzheimer’s and dementia is estimated to be $605 billion, which is equivalent to 1% of the entire world’s gross domestic product. According to the data from Alzheimer’s Association, people with Alzheimer’s disease are hospitalized three times more often than people without Alzheimer’s, the caregivers have estimated $236 billion in additional health care costs of their own in 2016. These numbers will escalate rapidly in coming years. By 2030, it is estimated that there will be 74.7 million people with dementia, and the cost of caring these individuals could rise to some US$2 trillion [1]. By 2050, the number of people age 65 and older with Alzheimer's disease may nearly triple, barring the development of medical breakthroughs to prevent or cure the disease.

The etiology of Alzheimer disease, which is multi-faceted, other than older age and genetic susceptibility, remains unclear. In the past decade, large strides have been made towards a better understanding of the pathogenesis of AD for possible interventions to delay the course of disease. While AD is rare in young individuals, especially below age 60 years, mutations in known early-onset genes are reported to contribute to ~50% of early-onset cases [2]. Incidence of AD increases with age in all populations [3, 4] with annual incidence in US increasing from ~1% at ages 65-70 years, to 6–8% by age 85 years and up [5, 6]. Although aging is the primary risk factor for AD, there are many other risk factors that may affect the progression of AD. 1) Researches have shown that adults with Type 2 diabetes mellitus (T2D) have a higher risk of later developing Alzheimer's and neurodegeneration compared with healthy individuals [7] and T2D is associated with a progressive cognitive decline [8]. Some work has suggested that brain insulin resistance may be an early and common AD marker [9] a...