J Pharm Pharm Sci (www.cspsCanada.org) 20, 184 - 225, 2017 Alzheimer’s Disease: Dawn of a New Era? Farideh Amirrad, Emira Bousoik, Kiumars Shamloo, Hassan Al-Shiyab, Viet-Huong V. Nguyen, Hamidreza Montazeri Aliabadi. School of Pharmacy, Chapman University, Irvine, CA, USA. Received, March 29, 2017; Revised, June 20, 2017; Accepted, July 8, 2017; Published, July 9, 2017. ABSTRACT - Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by a progressive decline in cognition and memory, leading to significant impairment in daily activities and ultimately death. It is the most common cause of dementia, the prevalence of which increases with age; however, age is not the only predisposing factor. The pathology of this cognitive impairing disease is still not completely understood, which has limited the development of valid therapeutic options. Recent years have witnessed a wide range of novel approaches to combat this disease, so that they greatly increased our understanding of the disease and of the unique drug development issues associated with this disease. In this paper, we provide a brief overview of the history, the clinical presentation and diagnosis, and we undertake a comprehensive review of the various approaches that have been brought to clinical trials in recent years, including immunotherapeutic approaches, tau-targeted strategies, neurotransmitter-based therapies, neurotropic and hematopoietic growth factors, and antioxidant therapies, trying to highlight the lessons learned from these approaches. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page. _______________________________________________________________________ INTRODUCTION approaches. In this manuscript, we focus mainly on the therapeutic approaches that have entered clinical The progressive growth of the elderly population trials. associated with constant increase in life expectancy, our limited understanding of the underlying History mechanisms involved in the etiology of the disease, Age-related dementia has been recognized since and the lack of reliable and effective preventive and ancient times. One of the earliest references to disease-modifying therapies available, has rendered dementia occurring with age is attributed to Alzheimer’s disease (AD) one of the great health Pythagoras, a 7th century BC Greek physician. challenges of the 21st century. AD is an Pythagoras divided the human life cycle into five irreversible neurological disorder that destroys stages commencing at ages 7, 21, 49, 63, and 81 cognitive function including loss of memory, years-old, describing the last two stages of life as judgment, reasoning, and behavioral control (1). It the “senium”, a period characterized by a regression has serious impact on social functioning, disruption in mental capacity and a return to the “imbecility of of quality of life, and impairment of activities of the first epoch of infancy” (4). In 500 BC, the daily living. It is the most common cause of Greek Judge Solon recognized the impairments on dementia that begins slowly and worsens over time decision making process that could be brought upon with a prevalence that increases with age (2). A by old age, revised laws regarding inheritances and complex set of cellular events, including feedback added the provision that “judgment … [be] not and feedforward responses of astrocytes, microglia, _________________________________________ and vasculature might be involved in the etiology of Corresponding Authors: Hamidreza Montazeri Aliabadi, AD, which has recently been reviewed by Strooper PhD, School of Pharmacy Chapman University; #211, 9401 Jeronimo Road; Irvine, CA 92618, USA. E-mail: and Karran (3). Increased understanding of the [email protected]; Viet-Huong V. Nguyen, PharmD, underlying mechanisms involved in the etiology of MPH, MS, BCPS, Chapman University School of Pharmacy; the disease during past two decades has led to the 9401 Jeronimo Road Rm 221; Irvine, CA 92618, USA. E-mail: development of a wide range of novel therapeutic [email protected] - The first three authors contributed equally to this work. 184 J Pharm Pharm Sci (www.cspsCanada.org) 20, 184 - 225, 2017 impaired by pain, violence, drugs, old age, or the cause of death calling it a “major killer” (7). In persuasion of a woman” in the making of wills (5). 1993, apolipoprotein E (APOE), which is located on In the 13th Century, Friar Roger Bacon recognized chromosome 19, was the first gene found to be that “age is the home of forgetfulness” and that loss related to the risk of Alzheimer`s. Other genes of memory and cognitive function was related to a were subsequently found to be linked to AD (8) disorder of the brain and not the heart, dispelling identifying possible genetic etiologies for some common notions of that time (4). However, he forms of AD. further recognized that specific cognitive deficits may be attributed to injuries in different brain areas Epidemiology (6). Dementia, as an abnormal process of aging It is estimated that approximately 44 million people was first recognized in 1901 by Dr. Alois worldwide are living with Alzheimer's disease. Alzheimer, after whom Alzheimer’s disease is However, only 11 million have been officially named. At that time, Dr. Alzheimer began treating a diagnosed with AD. Women are more likely to 51-year old woman named Auguste who had develop Alzheimer's disease than men of the same symptoms of short-term memory loss and age. Alzheimer's disease is most common in confusion. Dr. Alzheimer followed her case until Western Europe, followed by North America, and is she died in 1906, after which he studied her brain least prevalent in sub-Saharan Africa (9). The and determined that her problem was not caused by global cost of AD and dementia was estimated at normal dementia due to aging, but a larger health 605 billion dollars in 2015. From 2000-2013, AD issue. She was the first confirmed case of was the 6th leading cause of death in the United Alzheimer’s disease. In 1976, neurologist Dr. States (10), and it is expected to be the third leading Robert Katzman, a pioneer in Alzheimer’s research, cause of death of elderly after cancer and heart identified Alzheimer’s as the most common form of disease. AD is also the only disease in the top ten dementia and proposed that it may be a common causes of death that cannot be stopped, Figure 1. Statistical data for Alzheimer’s disease in United States, based on the data extracted from [10]. 185 J Pharm Pharm Sci (www.cspsCanada.org) 20, 184 - 225, 2017 cured, or prevented. Among 5.3 million Americans of AD include amyloid deposits consisting of with AD, 5.1 million are aged 65 and older. Figure amorphous aggregates of misfolded amyloid-beta 1 summarizes the distribution of AD based on age, (Aβ) protein (29). The “Amyloid Hypothesis” gender, and race. assumes a central role for Aβ in the pathogenesis of AD and characterizes AD as a “protein misfolding Etiology disease” which leads to aggregation and toxic The etiology of AD is uncertain; however, genetics, accumulation of Aβ in the brain (17, 18). However, environmental, and developmental components are although accumulation of Aβ has been linked to likely to play a role. The greatest risk factor for AD AD; the role of the protein in AD is not entirely is advancing age, although genetics has also been clear. extensively studied. Mutations in three genes, Aβ is produced from a precursor protein known amyloid precursor protein (APP), presenilin (PS)-1 as amyloid precursor protein (APP), a highly and PS-2 (both affecting APP processing and conserved membrane protein mainly expressed production of amyloid-beta peptides), cause early- around the synapse of neuronal tissue (19). APP onset (<60 years) autosomal dominant AD. Early seems to be involved in neuronal plasticity and onset-AD, however, accounts for only 1% of AD synapse formation (20). It is metabolized via two cases (11). Late-onset AD (>60 years) has most distinct pathways: (i) non-amyloidogenic pathway often been genetically linked to apolipoprotein (due to the non-aggregating nature of the products); (Apo) E ɛ4. Apo E4 has a gene-dose effect on and (ii) amyloidogenic pathway responsible for Aβ increasing the risk and lowering the age of both synthesis. The non-amyloidogenic metabolic familial and sporadic forms of late-onset AD. pathway is initiated by α-secretase and further While Apo E4 is the top gene associated with late processed by γ-secretase, which are members of a onset-AD gene, other genes that may modulate the family of proteolytic proteins with a disintegrin and risk of late-onset AD include CLU, CR1, PICALM, metalloprotease domain (ADAM) (21). The BIN1, SORL1, GAB2, ABCA7, MS4A4/MS4A6E, amyloidogenic pathway is initiated through CD2AP, CD33, APHA1, and HLA-DRB1/5. Other cleavage of APP by β-secretase (also known as risk factors for AD include head trauma, female beta-site APP cleaving enzyme; BACE1), and again gender, learning disabilities, education level, processed by γ-secretase (22). The Aβ fragments homocysteine levels, socioeconomic status, and from the amyloidogenic pathway accumulate to previous depression (12). Importantly, vascular risk form hard, insoluble plaques that are toxic to factors including diabetes and hyperlipidemia are neurons, and can lead to neuronal death. additional risk factors for AD (13, 14). However, Aβ clearance is also affected by the age and the Apo E4 allele continue to be the most Apoliprotein E (ApoE), a lipid binding protein significant risk factors for the development of AD involved in the transportation of cholesterol and along with female sex (15). The greater prevalence triglycerides to different tissues, including brain of AD in women could be attributed to the higher (23). Aβ binds to various regions of ApoE, and life expectancy in women, since the incidence of each Aβ-ApoE complex then participates in a AD in earlier ages is comparable between sexes different metabolic pathway, which includes: (1) (16).