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Towards understanding Alzheimer's Disease: An Overview

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Alzheimer's disease is the most frequent neurodegenerative disorder and the most common cause of dementia in the elderly. Diverse lines of evidence suggest that amyloid-β (Aβ) peptides have a causal role in its pathogenesis, but the underlying mechanisms remain uncertain. Recent evidence shows that Aβ may be part of a mechanism controlling synaptic activity, acting as a positive regulator presynaptically and a negative regulator postsynaptically. The pathological accumulation of oligomeric Aβ assemblies depresses excitatory transmission at the synaptic level, but also triggers aberrant patterns of neuronal circuit activity and epileptiform discharges at the network level. Aβ-induced dysfunction of inhibitory interneurons likely increases synchrony among excitatory principal cells and contributes to the destabilization of neuronal networks. Strategies that block these Aβ effects may prevent cognitive decline in Alzheimer's disease. Potential obstacles and next steps toward this goal are discussed. This review will discuss the case study, types and prevelance of Alzheimer’s disease pathogenesis.
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Research Journal of Pharmaceutical, Biological and Chemical
Sciences
Towards understanding Alzheimer's Disease: An Overview
Mayur Bagad, Debajyoti Chowdhury and Zaved Ahmed Khan *
Medical Biotechnology Division, School of Biosciences and Technology, Vellore Institute of Technology University,
Vellore, Tamil Nadu, India.
ABSTRACT
Alzheimer's disease is the most frequent neurodegenerative disorder and the most common cause of
dementia in the elderly. Diverse lines of evidence suggest that amyloid-β (Aβ) peptides have a causal role in its
pathogenesis, but the underlying mechanisms remain uncertain. Recent evidence shows that may be part of a
mechanism controlling synaptic activity, acting as a positive regulator presynaptically and a negative regulator
postsynaptically. The pathological accumulation of oligomeric assemblies depresses excitatory transmission at
the synaptic level, but also triggers aberrant patterns of neuronal circuit activity and epileptiform discharges at the
network level. Aβ-induced dysfunction of inhibitory interneurons likely increases synchrony among excitatory
principal cells and contributes to the destabilization of neuronal networks. Strategies that block these Aβ effects
may prevent cognitive decline in Alzheimer's disease. Potential obstacles and next steps toward this goal are
discussed. This review will discuss the case study, types and prevelance of Alzheimer’s disease pathogenesis.
Keywords: Amyloid-β (Aβ) peptides, Alzheimer's disease (AD).
*Corresponding author
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INTRODUCTION
Alzheimer's is the most common form of dementia, a general term for memory loss and
other intellectual abilities serious enough to interfere with daily life. Alzheimer's disease
accounts for 50 to 80 percent of dementia cases. It is estimated that by the year 2020,
approximately 70% of the world’s population aged 60 and above will be living in developing
countries, with 14.2% in India [1]. One in eight people age 65 and older (13 percent) has
Alzheimer’s disease, nearly half of people age 85 and older (45 percent) have Alzheimer’s
disease, an estimated 4 percent are under age 65, 6 percent are 65 to 74, 44 percent are 75 to
84, and 46 percent are 85 or older [2]. The figure includes 5.2 million people age 65 and older
and 200,000 individuals under age 65 who have younger-onset Alzheimer’s *3,4+. Alzheimer’s
disease is without doubt one of the most terrible afflictions of late middle age to old age. It has
often (on the analogy of heart failure) been termed ‘brain failure’. Alzheimer’s disease is a
neurodegenerative disorder characterized by cognitive deficit and loss of memory [5].
Clinical manifestations of AD are severe impairments in thought, learning, memory and
language abilities. The neuropathological hallmarks of AD are characterized by extracellular
deposition of the amyloid beta (Aβ) peptide in senile plaques, presence of intracellular
neurofibrillary tangles (NFTs) tau proteins, and neuronal loss [6]. The abnormal processing of
the amyloid precursor protein (APP) is the initiating event in AD pathogenesis, subsequently
causing aggregation of Aβ, specifically Aβ42 [7]. Amyloid beta-peptide *Aβ(1–42)], elevated in
AD brain, is associated with oxidative stress and neurotoxicity [6,7].
This review will provide a description of Alzheimer’s disease and its types, its
measurement and present the prevalence and incidence of Alzheimer’s disease in India and the
world. The burden of Alzheimer’s disease in India will be explored. Risk factors for Alzheimer’s
disease, co-morbid conditions, best management practice and treatment of Alzheimer’s disease
will be also included.
First case study with Alzheimer’s disease:
The first description of AD was given by Alois Alzheimer in 1907. His words are worth
quoting:
A woman of 51 years old, showed jealousy towards her husband as the first noticeable
sign of the disease. Soon a rapidly increasing loss of memory could be noticed. She could not
find her way around in her own apartment. She carried objects back and forth and hid them. At
times she would think that someone wanted to kill her and would begin shrieking loudly. In the
Institution her entire behavior bore the stamp of utter perplexity. She was totally disorientated
to time and place. Occasionally she stated she could not understand and did not know her way
around. At times she greeted the doctor like a visitor, and excused herself for not having
finished her work; at other times she shrieked loudly that he wanted to cut her, or she repulsed
him with indignation, saying that she feared something against her chastity. Periodically she
was totally delirious, dragged her bedding around, called her husband and her daughter, and
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seemed to have auditory hallucinations. Frequently, she shrieked with a dreadful voice for
many hours. Her ability to remember was severely disturbed. If one pointed to objects, she
named most of them correctly, but immediately afterwards she would forget everything. When
reading she went from one line to another, reading the letters or reading with a senseless
emphasis. When talking she used perplexing phrases and some periphrastic expressions (milk-
pourer instead of cup). Sometimes one noticed her getting stuck. Some questions she obviously
did not understand. She seemed no longer to understand the use of some objects [8,9].
TYPES OF ALZHEIMER'S DISEASE
Early-onset Alzheimer's:
This is a rare form of Alzheimer's disease in which people are diagnosed with the disease
before age 65. Less than 10% of all Alzheimer's disease patients have this type. Because they
experience premature aging, people with Down syndrome are particularly at risk for a form of
early onset Alzheimer's disease. Adults with Down syndrome are often in their mid to late 40s
or early 50s when symptoms first appear. Early- onset Alzheimer’s appears to be linked with a
genetic defect on chromosome 14, to which late-onset Alzheimer’s is not linked. A condition
called myocloms- a form of muscle twitching and spasm which is more commonly seen in early-
onset Alzheimer's than in late-onset Alzheimer's [10].
Inherited Alzheimer's is also referred to as familial Alzheimer's disease (FAD). Mutations
on three genes have been linked to familial, early-onset Alzheimer's disease. These genes have
been labeled PS1, PS2 and APP by researchers. Research from the 1990s indicates that
mutations on a gene labeled PS1 may be responsible for 30% to 60% of early-onset Alzheimer's
cases. Newer research is inconclusive regarding the exact prevalence of specific mutations, but
confirms that a PS1 gene is the mutation most commonly linked to FAD. The early indicators of
early-onset Alzheimer's disease are similar to those of late-onset Alzheimer's. These symptoms
include regularly losing items, difficulty executing common tasks, forgetfulness, personality
changes, confusion, poor judgment, challenges with basic communication and language, social
withdrawal and problems following simple directions [10,11].
Late-onset Alzheimer's:
This is the most common form of Alzheimer's disease, accounting for about 90% of cases
and usually occurring after age 65. Late-onset Alzheimer's disease strikes almost half of all
people over the age of 85 and may or may not be hereditary. Late-onset dementia is also called
sporadic Alzheimer's disease [12]. The cause of late-onset Alzheimer’s are not yet completely
understood, but they likely include a combination of genetic, environmental, and lifestyle
factors that influence a person’s risk for developing the disease [13].
PREVALENCE INDIAN SCENARIO:
According to the Delphi census, 93.1 million older people over 60 years of age, globally
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were estimated to be living with dementia; an overall prevalence of 1.6 % [14]. The Delphi
census estimated that in India, 3.7 million people aged over 60 have dementia [14]. Evidence
based on more than 42,000 older people studied in eight centres (5 urban and 4 rural areas)
across India, suggests that Ballabgarh and Vellore have the lowest estimated prevalence rates
whilst Tiruvandrum and Thiropour have the highest rates (Table 1) [15].
Setting
Location
Preference
References
Urban
Chennai
0.9% for age > 65
19
Kochi
3.3% for age > 65
20
Kolkata
1% for age > 60
21
Mumbai
2.3 % for age > 65
22
Trivandrum
4.8% for age > 65
23
Rural
Ballabgarh (Delhi)
3.1% for age > 60
24
Thiropour-semi rural (Tamil Nadu)
3.5% for age > 60
25
Ernakulum (Kerala)
3.1% for age > 60
26
Vellore (Tamil Nadu)
0.8% for age > 65
19
Table-1: Prevalence rates for dementia in India.
3.7 million Indian people aged over 60, 2.1 million are women 1.5 million men [16]. It is
argued that this cannot be explained by the fact that women live longer in India, because,
studies of age-specific incidence of dementia among older people show no significant
differences between women and men [17]. The prevalence of dementia increases steadily
with age and higher prevalence is seen among older women compared with men (figure 1).
Figure 1: Prevalence of Dementia for India by Age and Gender, 2012 [10,18].
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SYMPTOMS OF DISEASE
It may be hard to know the difference between a typical age-related change and the
first sign of Alzheimer’s disease. Major 10 warning signs for Alzheimer’s disease *27+ are listed:
Memory loss that disrupts daily life: Forgetting recently learned information important dates
or events. (Typical age-related change- Sometimes forgetting names or appointments, but
remembering them later.)
Challenges in planning or solving problems - Some people may experience changes in their
ability to develop and follow a plan or work with numbers. (Typical age-related change-making
occasional errors when balancing a checkbook.)
Difficulty completing familiar tasks at home, at work or at leisure - Hard to complete daily
tasks. (Typical age-related change-occasionally needing help to use the settings on a microwave
or to record a television show.)
Confusion with time or place - People with AD can lose track of dates, seasons and the passage
of time. (Typical age-related change- Getting confused about the day of the week but figuring it
out later.)
Trouble understanding visual images and spatial relationships - vision problems, difficulty
reading, judging distance and determining color or contrast are signs of Alzheimer’s. (Typical
age-related change- Vision changes related to cataracts.)
New problems with words in speaking or writing - May have trouble for joining a conversation.
They may struggle with vocabulary, have problems finding the right word or call things by the
wrong name (e.g., calling a watch a “hand clock”). (Typical age-related change- sometimes
having trouble finding the right word.)
Misplacing things and losing the ability to retrace steps - A person with AD may put things in
unusual places. (Typical age-related change- misplacing things from time to time, such as a pair
of glasses or the remote control.)
Decreased or poor judgment - They may experience changes in judgment or decision making.
(Typical age-related change- making a bad decision once in a while.)
Withdrawal from work or social activities - They may start to remove themselves from
hobbies, social activities, work projects or sports. (Typical age-related change- sometimes
feeling weary of work, family and social obligations.)
Changes in mood and personality - The mood and personality of people with AD can change.
They can become confused, suspicious, depressed, fearful or anxious. They may be easily upset
at home, at work, with friends or in places where they are out of their comfort zone. (Typical
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age-related change-developing very specific ways of doing things and becoming irritable when
a routine is disrupted.)
Fig 2: Brain Atrophy in Advanced Alzheimer’s Disease [41]
CAUSES OF DISEASE
Basics and Environmental risk factors:
The greatest known risk factor for Alzheimer’s is increasing age. Most individuals with
the illness are 65 and older. After age 85, the risk reaches nearly 50 percent. Another risk factor
is family history. Research has shown that those who have a parent, brother or sister with
Alzheimer’s are two to three times more likely to develop the disease. The risk increases if
more than one family member has the illness. The genes that directly cause the disease have
been found in only a few hundred extended families worldwide and account for less than 5
percent of cases. Experts believe the vast majority of cases are caused by a complex
combination of genetic and nongenetic influences [28]. During the 1960s and 1970s, aluminum
emerged as a possible suspect in causing Alzheimer’s disease. This suspicion led to concerns
about everyday exposure to aluminum through sources such as cooking pots, foil, beverage
cans, antacids and antiperspirants. Since then, studies have failed to confirm any role for
aluminum in causing Alzheimer’s. Almost all scientists today focus on other areas of research,
and few experts believe that everyday sources of aluminum pose any threat [28, 29].
Environmental exposure to some heavy metals such as cadmium appears to be a risk factor for
Alzheimer's disease (AD), though, definite mechanism of their toxicity in AD remains to be
elucidated. The impacts of Cd(II) on the conformation and self-aggregation of Alzheimer's tau
peptide R3, corresponding to the third repeat of microtubule-binding domain has revealed [29].
The initial state of R3 was proven to be dimeric linked by intermolecular disulfide bond, in the
non-reducing buffer (TrisHCl buffer pH7.5, containing no reducing reagent). The Cd(II) can
accelerate heparin-induced aggregation of R3 or independently induce the aggregation of R3,
as monitored by ThS fluorescence. In the presence of Cd(II), the resulting R3 filaments became
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much smaller, as revealed by electron microscopy. Binding to the Cd(II) ion, the dimeric R3
partially lost its random coil, and converted to α-helix structure, as revealed by CD and Raman
spectrum *29+. On the other hand, gain in α-helix structure on the peptide chain, by
coordinating with Cd(II), could be a critical role to promote self-aggregation, as revealed by
Raman spectrum. These results provide a further insight into the mechanism of tau filament
formation and emphasize the possible involvement of Cd(II) in the pathogenesis of AD [28, 29].
Amyloid hypothesis:
Alzheimer’s disease and cerebral amyloid angiopathy are characterized by the
deposition of β-amyloid fibrils consisting of 40- and 42-mer peptides (Aβ 40 and 42). The
aggregation (fibrilization) of these peptides is closely related to the pathogenesis of these
diseases *30+. Aβ 42 plays a more important role in the pathogenesis of these diseases since its
aggregative ability and neurotoxicity are considerably greater than those of -40. Aβ peptides
result from the proteolytic cleavage of β -amyloid precursor protein (APP) [31] by two
proteases, β and γ-secretase [32-34+. Under physiological conditions, the ratio of Aβ 42 to
40 is about 1:10. Aβ 42 plays a critical role in the pathogenesis of AD since its aggregative ability
and neurotoxicity are much greater than those of Aβ 40 *33, 36+. Aβ 42 oligomers initially
formed as a seed accelerate the aggregation of Aβ 40 to form the amyloid plaques that
eventually lead to the neurodegeneration (amyloid cascade hypothesis) [37]. Although the
direct involvement of Aβ peptides in AD is well documented and their aggregative ability is
closely related to their neurotoxicity, the precise mechanism of the neurotoxic effects of
peptides remains unclear. Moreover, it has recently been reported that the neurotoxicity of Aβ
peptides might be ascribable to the oligomeric species, not the fibrils [38, 39]. The structural
analysis of Aβ fibrils is one of the most promising ways of revealing the mechanism of AD.
Recent biophysical investigations using electron microscopy, Fourier transform infrared
spectroscopy (FT-IR), and circular dichroism (CD) spectroscopy showed that Aβ fibrils adopt a β
-sheet structure [39]. However, a high-resolution structural analysis of fibrils has yet to be
conducted since single crystal X-ray crystallography and solution NMR cannot be applied to
insoluble Aβ fibrils.
Tau hypothesis:
Alzheimer’s disease (AD) (Alzheimer, 1907) is a neurodegenerative disease which is
characterized by the presence of two types of neuropathological hallmarks: neurofibrillary
tangles (NFTs) and senile plaques [40]. It is collectively designated as ‘‘tauopathies’’, because
they are characterized by the aggregation of abnormally phosphorylated tau protein. NFTs are
intraneuronal aggregates of abnormally phosphorylated tau (phosphorylated at non
physiological sites). Senile plaques are extracellular and mainly composed of amyloid β -peptide
(Aβ) deposits. The mechanisms responsible for tau aggregation and its contribution to
neurodegeneration are still unknown. The regulation of tau takes place predominantly through
post-translational modifications. To aggregate into PHFs (paired helical filaments), tau affinity
for microtubules must be decreased to release tau in a soluble form. Dissociation of tau from
microtubules, probably by phosphorylation, results in microtubule destabilization. Then, newly
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soluble tau proteins are targeted by post-translational modifications that directly or indirectly
alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau
dimers form tau oligomers, which continue in the aggregation process and constitute subunits
of filaments, called protomers. Two protomers around each other formed PHFs and PHFs
assembly makes NFTs [40]. As a result of neuronal death, tau oligomeric species are released
into the extracellular environment, thus contributing to microglial activation and providing
positive feedback on the deleterious cycle that lead to progressive degeneration of neurons in
AD brains [41]. Therefore, information obtained in the process of testing this new hypothesis
experimentally will likely be helpful to formulate an innovative AD therapy and to design
reliable biomarker strategies for its diagnosis.
Tau gene, mRNA and protein structures:
Tau protein (tubulin-associated unit) was identified in 1975 [39,42]. Tau is a
microtubule-associated protein highly conserved and exclusively found in higher eukaryotes
[39]. Tau is mainly expressed in neuron and its primary role is to stabilize neuronal cytoskeleton
by interacting with microtubules. Tau is encoded by a single gene located in locus 17q21.3 in
human [43]. Among the 16 exons of tau gene, exons 2, 3 and 10 undergo alternative splicing,
whereas exon 4A is only transcribed in the peripheral nervous system [39, 44, 45]. To date,
exons 6 and 8 have not been described to be transcribed [44]. In the central nervous system,
alternative splicing of tau primary transcript generates six isoforms of 352441 amino acids
with an apparent molecular weight between 60 and 74 kDa [39]. Exon 14 is transcribed but
generates a premature stop codon preventing translation [44].
Depending on the presence or absence of exon 10, tau isoforms are called 4R (with exon
10) or 3R (without exon 10) [39]. Tau isoforms are called 0N (without N-terminal insert), 1N
(with one N-terminal insert encoded by exon 2) or 2N (with two N-terminal inserts encoded by
exons 2 and 3). This gives six combinations corresponding to the six tau isoforms: 4R/2N,
4R/1N, 3R/2N, 4R/0N, 3R/1N and 3R/0N. Each repeat domain contains a conserved consensus
motif KXGS, which can be phosphorylated at serine [46]. Serine phosphorylation at KXGS motifs,
belonging to MBD region, decreases tau affinity for microtubules and consequently prevents its
binding to microtubules which results in the destabilization of the neuronal cytoskeleton [47].
Cytoskeleton destabilization is well known to cause disruption of tau-dependent cellular
functions including axonal growth, vesicle and organelle transport as well as nervous signal
propagation along the nerve network formed by microtubules [48].
TREATMENT
Approved drugs in markets:
Alzheimer’s disease is a devastating neurodegenerative disorder manifested by
deterioration in memory and cognition, impairment in performing activities of daily living, and
many behavioral and neuropsychiatric illnesses. The pathological hallmark of Alzheimer’s
disease is widespread neuritic plaques which are accumulations of amyloid beta protein and
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neurofibrillary tangles. Studies report that deficit in cholinergic system is responsible for
cognitive decline and memory loss in patients with Alzheimer’s disease. The leading edge
therapies of Alzheimer’s disease are approved drugs listed in table 2 *49+.
Drugs used in Alzheimer’s disease
Cholinesterase
Inhibitors
Donepezil
Rivastigmine
Galantamine
Physostigmine
Tacrine
NMDA
Antagonist
Memantine
New
Cholinesterase
Inhibitors
Phenserine
Tolserine
Esolerine
Tasofensine
Standard Drugs
(Role well established) Experimental Drugs
(Under Appraisal)
Antioxidant
Gingko biloba
Vitamin E
Melatonin
α-lipoic acid
Nicotinic
Receptors
Agonists
Varenicline
4OH-GTS-21
Gamma
Secretase
Inhibitors
Semagacestat
Avagacestat
PPAR Gamma
Agonist
Pioglitazone
Statins
Simvastatin
Pravastatin
5 HT-
Antagonist
SB-271046
Others
Estrogens
Heavy metal
chelators
Fig. 2: Drugs used in Alzheimer’s disease.
The pharmacological agents used for treatment of Neuropsychiatric illnesses include
antipsychotics, antidepressants and mood stabilizers. Treatment of Alzheimer’s disease also
includes health maintenance activities and proper nursing care of the patients.
Treatment -Alternative forms of medicine:
There are several non pharmacological strategies, which manage the functional and
behavioral deterioration (www.gmhfonline.org). A recent review has suggested that there is
evidence to support the efficacy of activity programs, music, behavior therapy, light therapy
and changes to the physical environment [50].
Independence promoting strategies: Usage of incentives, verbal and physical prompting and
physical guidance. Helps the patient in maintaining hygiene, dressing, grooming etc.
Exercise: Simple exercises like walking and cycling can improve sleep and decrease agitation.
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Incontinence management: By monitoring incontinence and scheduling bathroom time or by
putting reminders.
Sleep management: Enhance night time sleep by dark environment at night and limiting day
time napping.
White noise: Continuous background monotonous noise reduces agitation and is soothing.
Music therapy also helps to stir memories.
Visual cueing- Pasting pictures of bed on bedroom door can help the patient find his way
around home.
Counseling, reminiscence therapy, validation, simulated presence, pet therapy,
recreational therapy and art therapy are other ways of reducing behavioral swings in a patient
suffering from Alzheimer disease.
APPLICATION OF MODERN TECHNOLOGY FOR DIAGNOSIS AND TREATMENT UNDER
DEVELOPMENT-HYPOTHESIS
Cell based therapy:
Skin cells from patients with Alzheimer’s disease have been reprogrammed to form
brain cells, offering clues to their dementia and the prospect of early diagnosis and new ways of
finding treatments. Goldstein and his team created Induced pluripotent stem (IPS) cells from
four patients with AD and two people without dementia. IPS cells are made by treating
fibroblasts, a type of skin cell, with reprogramming factors to revert them to an embryonic-like
state. Like the stem cells in early embryos, IPS cells can form any tissue in the body including
neurons *51+. The researchers generated neurons from patients with two types of Alzheimer’s:
familial, which is caused by inherited, rare mutations in specific genes, and sporadic, which
results from an interplay of genetic and environmental factors. The reprogrammed neurons
from the patients with familial AD have showed defects that had been seen before in the brains
of Alzheimer's patients. Compared to unaffected cells, their neurons produced higher levels of
amyloid-β, a protein that builds up and forms plaques in patients with Alzheimer’s. This is not
surprising, as their mutation is in a gene that encodes amyloid-β. But their neurons also
produced high amounts of another protein, tau, which forms tangles in the brains of patients
[51].
Many researchers are concerned that these "disease-in-a-dish" models based on IPS
cells may not be true reflections of the disease, but may be artifacts from the reprogramming
process.
Antibodies could be key defenders against Alzheimer's, recent evidence [42]
The newly found antibodies selectively target aggregates of beta amyloid proteins that
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are toxic to brain cells, while ignoring the benign single-molecule forms of the same proteins.
The existence of such antibodies was predicted by animal studies, but they were never
previously demonstrated to be present in substantial quantities in blood from normal humans.
Relkin's team [52] has been testing an antibody-based immunotherapy called intravenous
immunoglobulin (IVIg), which is made from the blood of healthy donors, as a potential new
treatment for Alzheimer's.[52] Since IVIg was known to contain small amounts of antibodies
against β-amyloid, the researchers hoped for a correspondingly modest reduction in the
harmful plaques in Alzheimer's patients. Studies demonstrated that IVIg initially bound very
little single-molecule (monomer) β-amyloid in a test tube [52]. However, it gathered up much
more of the protein when the amyloid was aged in a way that allowed clumps of many
molecules -- called oligomers -- to form. These oligomers can grow into the insoluble fibers that
cluster around brain cells; a hallmark of Alzheimer's. While monomers are produced from birth
and appear to be relatively benign, the oligomers have been implicated as potent toxins
responsible for Alzheimer's-linked memory loss and brain cell death [52].
CONCLUSION
Over the last two decades, tremendous knowledge has been gained on AD, and its
diagnosis, pattern of care, epidemiology, and economic impact. Alzheimer disease is one of the
most debilitating diseases affecting the old age. A clear understanding of the natural history of
Alzheimer disease has enabled us to develop appropriate trial designs and outcomes for the
various stages of this condition. Clear benefit for the treatment of symptoms in mild to severe
AD using AChEIs and Memantine is seen. Also, there is cautious optimism for successful disease
modification using a number of agents currently under study. Guidelines for the treatment of
Alzheimer disease have to be constantly updated to take into account new evidence for the
ultimate benefit of patients and care-givers. As the population ages, the venue of new
treatments for the management of AD, as well as the reforms occuring in the health care
system, will force the integration of the current knowledge base with the aim of better
addressing the needs of patients with AD, and their families.
CONFLICT OF INTEREST STATEMENT
We declare that we have no conflict of interest.
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... EGCG a potential therapeutic agent for neurodegenerative diseases Neurodegenerative diseases are characterized by different structural and pathological conditions including the accumulation of modified or diseased proteins such as α-synuclein in PD [40], β-amyloid peptide and tau protein in AD [3,41] that further contribute towards inflammation [42], elevate expression levels of pro-apoptotic proteins [43,44], trigger glutamatergic excitotoxicity [45], iron accumulation [46] and oxidative stress [47]. It is therefore necessary to look for drugs capable of simultaneously manipulate multiple desired targets and exerting higher therapeutic effectiveness [48]. ...
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