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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
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.
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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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
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].
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].
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].
0.9% for age > 65
3.3% for age > 65
1% for age > 60
2.3 % for age > 65
4.8% for age > 65
Ballabgarh (Delhi)
3.1% for age > 60
Thiropour-semi rural (Tamil Nadu)
3.5% for age > 60
Ernakulum (Kerala)
3.1% for age > 60
Vellore (Tamil Nadu)
0.8% for age > 65
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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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]
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].
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
Standard Drugs
(Role well established) Experimental Drugs
(Under Appraisal)
Gingko biloba
Vitamin E
α-lipoic acid
PPAR Gamma
5 HT-
Heavy metal
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 ( 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.
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
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
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].
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.
We declare that we have no conflict of interest.
[3] World Health Organization, Active Ageing: a Policy Framework, World Health
Organization 2002, Geneva, Switzerland.
[4] LE Hebert, PA Scherr, JL Bienias, DA Bennett, and DA Evans. Arch Neurol 2000; 60: 1119
[5] Chandra V, Ganguli M, Pandav R et al. Neurology 1998; 51:10001008.
[6] Mittal G, Carswell H. Brett R. et al. J Cont Release 2011; 150: .220228.
ISSN: 0975-8585
October-December 2013 RJPBCS Volume 4 Issue 4 Page No. 297
[7] Jue He, Huanmin Lu and Bin Yan. Neurology Aging 2009; 30: 12051216.
[8] Smith C. U. M. John Wiley & Sons, Ltd, 2002.
[9] Bayreuther K and Masters C.L. Brain Res Rev 1991; 16: 8688.
[14] Ferri C.P, Prince M, Brayne C. et al. Lancet 2005; 366: 2112-2117.
[15] Dias A and Patel V. Ind J Psych 2009; 51(5): 93-97.
[16] Shaji KS. Ind J Psych 2009; 51(5): 5-7.
[17] Satishchandra P, Yasha T.C, Shankar L. et al. Alzheimer Disease and Associated Disorders
1997; 11(2): 107-109.
[18] Jotheeswaran A.T. Alzheimer's & Related Disorders Society of India 2010; Thrissur.
[19] Llibre J.J, Ferri C.P, Acosta D, Guerra M et al. Lancet 2008; 372: 464-474.
[20] Shaji S, Bose S, and Verghese A. British J Psyc 2005; 186:136-140.
[21] Das S.K, Biswas A, Roy T. et al. Ind J Med Res 2006; 124(2): 163-172.
[22] Prince M, Ferri C.P, Acosta D. et al. BMC Public Health 2007; 7:23-31.
[23] Mathuranath P.S, Cherian P.J, Mathew R. et al. Int J Ger Psyc 2010; 25(3): 290-297.
[24] COHEN L. Med Anthrop Quart 1995; 3: 334.
[25] Shaji S, Promodu K, Abraham T and Roy K.J. British J Psyc 1996; 168: 745-749.
[26] Rajkumar S, Kumar S and Thara R. Int J Ger Psyc 1997; 12(7): 702-707.
[27] Alloul K, Sauriol L, Kennedy W, et al. Arch Geront Geriat 1998; 27: 189-221.
[28] Relkin N. R, Szabo P, Adamiak B, et al. Neurob Aging 2009; 30: 1728-1736.
[30] Ling-Feng Jiang, Tian-Ming Yao, Zhi-Liang Zhu, et al. Bioch et Biophy Acta 2007; 1774:
[31] Kazuhiro I, Kazuma M, Masuda Y, et al. J Biosci Bioeng 2005; 99(5): 437447.
[32] Goate A, Chartier-Harlin M, Mullan M. et al. Nature 1991; 349: 704706.
[33] Iwatsubo T, Odaka A, Suzuki N, et al. Neuron 1994; 13: 4553.
[34] Iwatsubo T, Mann D, Odaka A, et al. Ann neurol 1995; 37: 294299.
[35] Vassar R, Bennett B, Babu-Khan S, et al. Science 1999; 286: 735 741.
[36] Davis J, and Van Nostrand. Proceeding of National Academy of Sciences 1996; 93: 2996
[37] Jarrett J.T, and Lansbury P.T. Cell 1993; 73: 10551058.
[38] Bucciantini M, Giannoni E, Baroni F, et al. Nature 2002; 416: 507511.
[39] Ludovic M, Xenia L and Faraj Terro. Neurochem Int 2011; 58: 458471.
[40] Maccioni R.B, Faris G, Morales I, and Navarrete L. Arch Med Res 2010; 41:226- 231.
[41] Morales I, Farias G, Maccioni R.B. Neuroimmunomodulation 2010; 17: 202- 204.
[42] Cleveland D.W, Hwo S.Y and Kirschner M.W. J Mol Biol 1997; 116: 207225.
[43] Almos P.Z, Horvath S, Czibula A, et al. Heredity 2008; 101: 416419.
[44] Buee L, Bussiere T, Buee-Scherrer V and Delacourte A. Brain Res Rev 2000; 33: 95130.
[45] Panda D, Samuel J.C, Massie M, Feinstein S.C, and Wilson L. Proceeding of the national
academy of sciences U. S. A. 2003; 100: 95489553.
[46] Ozer R. S, and Halpain S. Mol biol cell 2000; 11: 35733587.
ISSN: 0975-8585
October-December 2013 RJPBCS Volume 4 Issue 4 Page No. 298
[47] Dickey C.A, Kamal A, Lundgren K. et al. J Clin Invest 2007; 117: 648658.
[48] Gendron T.F. and Petrucelli L. Mol Neurodeg 2009; 4: 13.
[49] Mona Mehta, Abdu Adem, and Marwan Sabbagh. Int J Alz Dis 2011; 1:1-9.
[50] Upadhyaya P, Seth V and Ahmad M. Afr J Pharm Pharmacol 2010; 4(6): 408-421.
[51] Mason A, Yuan S.H, Bardy C, et al. Nature 2012; 482: 216220.
[52] Relkina N.R, Szaboa P, Adamiaka B, et al. Neurob Aging 2009; 30:17281736.
... 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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Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) enforce an overwhelming social and economic burden on society. They are primarily characterized through the accumulation of modified proteins, which further trigger biological responses such as inflammation, oxidative stress, excitotoxicity and modulation of signalling pathways. In a hope for cure, these diseases have been studied extensively over the last decade to successfully develop symptom-oriented therapies. However, so far no definite cure has been found. Therefore, there is a need to identify a class of drug capable of reversing neural damage and preventing further neural death. This review therefore assesses the reliability of the neuroprotective benefits of epigallocatechin-gallate (EGCG) by shedding light on their biological, pharmacological, antioxidant and metal chelation properties, with emphasis on their ability to invoke a range of cellular mechanisms in the brain. It also discusses the possible use of nanotechnology to enhance the neuroprotective benefits of EGCG.
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Alzheimer’s disease (AD) is related to cognitive impairment, dementia observed generally in aged population due to neurodegeneration in an ongoing manner. It gradually worsens memory power of the patient. The hallmark diagnosis features includes formation of senile plaques and Neurofibrillary tangles (NFT’S) [1, 2]. Too little availability of Acetyl choline (ACh) a neurotransmitter in the cerebral region due to metabolism by an enzyme Acetyl choline esterase before showing its action and neural death are the primary reasons for AD. There are many categories of Anti-Alzheimer’s drugs available for management of AD in the market but due to lack of patient compliance successful outcomes were not observed [3]. Apart from this including Nutraceuticals in diet daily routine, Aromatherapy, modifications in the regular schedule, practicing yoga regularly relaxes mind and body from tensions, insomnia, blood circulation, detoxification of organs due to rhythmic breathings and reduce frequency of incidence of headache are proven to show best results by relieving stress according to survey[4-9]. At present herbal medicine has turn out to be best choice for the management of AD because of its availability, very economic, good patient compliance, ease of formulation and lower deleterious side effects [10, 11]. Novel techniques can be used for the development of herbal medicine. This review totally discuses about the occurrence of AD, its Pathophysiology, different stages in the disorder, various selective therapeutic targets for AD, available Anti-AD herbal drugs such as Curcumin, Withania somnifera, Bhrami, Ginkgo biloba, guggul, ginseng, herbs with essential oils, volatile oils, source and cultivation of the herbs, mechanism of action of the Phytochemicals in the herb responsible for treating AD. Keywords: Alzheimer’s disease (AD), cognitive impairment, Dementia, Senile plaques, Nutraceuticals, Herbal medicine, Phytoconstituents.
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Background Data on the prevalence of dementia in India with a large and aging population is scant. We studied prevalence of AD and dementia in Kerala, South India, and effects of age, education and gender on it.Methods2-phase survey on 2466 individuals aged ≥ 55 years living in community. Men constituted 41%, < 75 years age in 76.9% and education ≥ 4 years in 69.6%. Screening (Phase I) using the instrumental activity of daily living scale for the elderly (IADL-E) and the Addenbrooke's cognition examination (ACE). Diagnostic-assessment (Phase II) was in 532 screen-positives and 247 (10%) screen-negatives.Results93 (3.77%) ≥ 55 years and 81 (4.86%) ≥ 65 years of age had dementia. Age adjusted (against US-population in 2000) dementia (and AD) rates were 4.86% (1.91%) in age ≥ 55 years and 6.44% (3.56%) in ≥ 65 years. Odds for dementia (and AD) were high with increasing-age 5.89 (15.33) in 75–84, 13.23 (25.92) ≥ 85 years, and in women 1.62 (2.95); and low 0.27 (0.16) if education was ≥ 9 years. Age and low education increased dementia. Age and female gender increased AD.Conclusion Prevalence of dementia and AD is higher than any reported from the subcontinent suggesting that dementia in Kerala in South India is not uncommon. Increasing age increased dementia and AD. Low-education is associated with dementia and female-gender with AD. Copyright © 2009 John Wiley & Sons, Ltd.
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Studies have suggested that the prevalence of dementia is lower in developing than in developed regions. We investigated the prevalence and severity of dementia in sites in low-income and middle-income countries according to two definitions of dementia diagnosis. We undertook one-phase cross-sectional surveys of all residents aged 65 years and older (n=14 960) in 11 sites in seven low-income and middle-income countries (China, India, Cuba, Dominican Republic, Venezuela, Mexico, and Peru). Dementia diagnosis was made according to the culturally and educationally sensitive 10/66 dementia diagnostic algorithm, which had been prevalidated in 25 Latin American, Asian, and African centres; and by computerised application of the dementia criterion from the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). We also compared prevalence of DSM-IV dementia in each of the study sites with that from estimates in European studies. The prevalence of DSM-IV dementia varied widely, from 0.3% (95% CI 0.1-0.5) in rural India to 6.3% (5.0-7.7) in Cuba. After standardisation for age and sex, DSM-IV prevalence in urban Latin American sites was four-fifths of that in Europe (standardised morbidity ratio 80 [95% CI 70-91]), but in China the prevalence was only half (56 [32-91] in rural China), and in India and rural Latin America a quarter or less of the European prevalence (18 [5-34] in rural India). 10/66 dementia prevalence was higher than that of DSM-IV dementia, and more consistent across sites, varying between 5.6% (95% CI 4.2-7.0) in rural China and 11.7% (10.3-13.1) in the Dominican Republic. The validity of the 847 of 1345 cases of 10/66 dementia not confirmed by DSM-IV was supported by high levels of associated disability (mean WHO Disability Assessment Schedule II score 33.7 [SD 28.6]). As compared with the 10/66 dementia algorithm, the DSM-IV dementia criterion might underestimate dementia prevalence, especially in regions with low awareness of this emerging public-health problem.
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In this study, we examine the frequency of a 900 kb inversion at 17q21.3 in the Gypsy and Caucasian populations of Hungary, which may reflect the Asian origin of Gypsy populations. Of the two haplotypes (H1 and H2), H2 is thought to be exclusively of Caucasian origin, and its occurrence in other racial groups is likely to reflect admixture. In our sample, the H1 haplotype was significantly more frequent in the Gypsy population (89.8 vs 75.5%, P<0.001) and was in Hardy-Weinberg disequilibrium (P=0.017). The 17q21.3 region includes the gene of microtubule-associated protein tau, and this result might imply higher sensitivity to H1 haplotype-related multifactorial tauopathies among Gypsies.
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Since the identification of tau as the main component of neurofibrillary tangles in Alzheimer's disease and related tauopathies, and the discovery that mutations in the tau gene cause frontotemporal dementia, much effort has been directed towards determining how the aggregation of tau into fibrillar inclusions causes neuronal death. As evidence emerges that tau-mediated neuronal death can occur even in the absence of tangle formation, a growing number of studies are focusing on understanding how abnormalities in tau (e.g. aberrant phosphorylation, glycosylation or truncation) confer toxicity. Though data obtained from experimental models of tauopathies strongly support the involvement of pathologically modified tau and tau aggregates in neurodegeneration, the exact neurotoxic species remain unclear, as do the mechanism(s) by which they cause neuronal death. Nonetheless, it is believed that tau-mediated neurodegeneration is likely to result from a combination of toxic gains of function as well as from the loss of normal tau function. To truly appreciate the detrimental consequences of aberrant tau function, a better understanding of all functions carried out by tau, including but not limited to the role of tau in microtubule assembly and stabilization, is required. This review will summarize what is currently known regarding the involvement of tau in the initiation and development of neurodegeneration in tauopathies, and will also highlight some of the remaining questions in need of further investigation.
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 neurofibrillary tangles. Studies report that deficit in cholinergic system is responsible for cognitive decline and memory loss in patients with Alzheimer's disease. Various pharmacologic approaches are developed for the treatment of Alzheimer's disease. The leading edge therapies of Alzheimer's disease are approved drugs; Acetylcholinesterase inhibitors and NMDA receptor antagonist. The experimental therapies are mostly disease modifying and have neuroprotective approaches. Gamma secretase inhibitors aim to reduce amyloid beta formation. Antioxidants, antiinflammatory agents and statins help by preventing oxidation and inflammation. PPAR gamma agonists, estrogen, heavy metal chelators, 5HT 6 antagonists and nicotinic receptor agonists are other therapeutic strategies likely to alter the current treatment paradigm of Alzheimer's disease. The behavioral abnormalities are best treated first by non-pharmacologic interventions. 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.
This article consists of a critical review of Canadian, American and European studies published between 1976 and 1997 on the subject of Alzheimer's disease (AD), and its epidemiology, patterns of care, prognostic factors, and economic impact. As the population ages in North America and Europe, significant increases in the prevalence of AD over the next decades have been projected. The elderly population represents the largest consumer group of health care resources and the management of common diseases occurring in this population will have major medical, social, and economic implications. As a result, researchers will need to integrate the ever-increasing knowledge on AD when addressing governmental and societal concerns regarding its impact. Described herein is the study findings, limitations, and differences observed following the review of the diagnostic criteria, prevalence rates, incidence rates and risk factors. Highlighted are the areas where data is lacking. To refine current models of disease progression, and better address where health care resources and new therapies would be most beneficial, the review of predictors of institutionalization and predictive models of disease progression and survival, was performed. New research questions are indicated.
There is a rich epidemiological evidence base on dementia in India which shows that this neurodegenerative condition is an important public health problem, particularly in the context of the rapid demographic transition in many parts of the country. Research has shown that most people with dementia, and their caregivers, have significant unmet health and social welfare needs. Due to the great shortage of health care resources and the low levels of awareness about dementia, interventions addressing the needs of the people should be home based and directed at improving quality of life of the person with dementia and the caregiver. In view of the lack of specialists to deal with dementia, a group in Goa developed an alternate model of care which involved training lay health workers to provide home-based care for people with dementia under the supervision of a psychiatrist. This was successfully implemented and evaluated in a randomized controlled trial which showed clear benefits. This article concludes by considering the implication of these findings on strategies for scaling up services and close the treatment gap for dementia in India.
The purpose of this study was to develop tween 80 (T-80) coated polylactide-co-glycolide (PLGA) nanoparticles that can deliver estradiol to the brain upon oral administration. Estradiol containing nanoparticles were made by a single emulsion technique and T-80 coating was achieved by incubating the re-constituted nanoparticles at different concentrations of T-80. The process of T-80 coating on the nanoparticles was optimized and the pharmacokinetics of estradiol nanoparticles was studied as a function of T-80 coating. The nanoparticles were then evaluated in an ovariectomized (OVX) rat model of Alzheimer's disease (AD) that mimics the postmenopausal conditions. The nanoparticles bound T-80 were found to proportionally increase from 9.72 ± 1.07 mg to 63.84 ± 3.59 mg with an increase in the initial concentration T-80 from 1% to 5% and were stable in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). Orally administered T-80 coated nanoparticles resulted in significantly higher brain estradiol levels after 24h (1.969 ± 0.197 ng/g tissue) as compared to uncoated ones (1.105 ± 0.136 ng/g tissue) at a dose of 0.2mg/rat, suggesting a significant role of surface coating. Moreover, these brain estradiol levels were almost similar to those obtained after administration of the same dose of drug suspension via 100% bioavailable intramuscular route (2.123 ± 0.370 ng/g tissue), indicating the increased fraction of bioavailable drug reaching the brain when administered orally. Also, the nanoparticle treated group was successful in preventing the expression of amyloid beta-42 (Aβ42) immunoreactivity in the hippocampus region of brain. Together, the results indicate the potential of nanoparticles for oral delivery of estradiol to brain.
Many hypotheses have been raised regarding the pathophysiology of Alzheimer's disease (AD). Because amyloid beta peptide (Abeta) deposition in senile plaques appears as a late, nonspecific event, recent evidence points to tau phosphorylation and aggregation as the final common pathway in this multifactorial disease. Current approaches that provide evidence in favor of neuroimmunomodulation in AD and the roles of tau pathological modifications and aggregation into oligomers and filamentous forms are presented. We propose an integrative model on the pathogenesis of AD that includes several damage signals such as Abeta oligomers, oxygen free radicals, iron overload, homocysteine, cholesterol and LDL species. These activate microglia cells, releasing proinflammatory cytokines and producing neuronal degeneration and tau pathological modifications. Altered and aggregated forms of tau appear to act as a toxic stimuli contributing to neurodegeneration. Recent findings provide further support to the central role of tau in the pathogenesis of AD, so this protein has turned into a diagnostic and therapeutic target for this disease.