ALZHEIMER’S DISEASE

AND ITS MANAGEMENT

Project Report

Submitted to the Faculty of Pharmaceutical Sciences

Pt. B. D. Sharma University of Health Sciences (Govt.
of Haryana) Rohtak-124001

for the award of the degree of

BACHELORS OF PHARMACY

By

ABHISHEK

South Point College of Pharmacy

NCR Delhi, Murthal Chowk G.T.Road, Murthal, Sonepat, Haryana - 131027
2019-2023

Registration no. Roll No.

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 FORWARDING CERTIFICATE

This is to certify that Mr. Abhishek S/O Mr. Surender Kumar a student of B.Pharmacy Final
Year in this college has worked on the project entitled

“Alzheimer’s disease and its management” under my guidance and supervisor

He has worked hard, meticulously and methodically. I wish him every success in future
endeavors and recommended that project work to be forwarded for evaluation

SUPERVISOR PRINCIPAL

Ms. ANJALI CHIKARA DR. ASHIMA HOODA

M.PHARM (PHARMACOLOGY) M.PHARMACY

P.HD PURSUING P.HD ( PHARMACEUTICS)

ASSISTANT PROFESSOR PRINCIPAL

SOUTH POINT COLLEGE OF SOUTH POINT COLLEGE OF

PHARMACY PHARMACY

SONIPAT, HARYANA SONIPAT , HARYANA

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Affectionately
Dedicated
To
GOD,
TEACHERS
and
my
FAMILY

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Saraswati Mantra...

"YaaKundendu Tushaara Haaradhavalaa, YaaShubhravastraavritha Yaa Veenavara

Dandamanditakara, YaaShwetha Padmaasana YaaBrahmaachyuthaShankaraPrabhritibhir
Devaisadaa Vanditha SaaMaam PaatuSaraswatiBhagavateeNihsheshaJaadyaapaha"

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 Acknowledgment

work on this project has been an inspiring often exciting, sometimes challenging, The but
always interesting and an enjoyable experience.

Thankfully, I've had the opportunity to work with a great many people who are far more
talented, dedicated and experienced than me at every step of the way. I know I can be quite a
handful at times, but many of my mentors have been generous enough with their time and trust
to permit me to pursue my own paths.

First of all, I would like to thank my supervisor Ms Anjali Chhikara, South Point College of
Pharmacy, who guided this project and helped whenever I was in need.

He has always had time for discussion and continually shown great interest in my research.
Among his absolutely best sides is her ability to stimulate one's imagination and creativity.

I owe a huge debt of gratitude to Mr. Dilbag Singh Khatri, Chairman, SouthPoint College of
Pharmacy for providing me all the facilities and encouragement for the successful completion
of my project work.

I would also like to thank Dr. Mamta Sachdeva, Director, South Point College of Pharmacy for
her outstanding advice and valuable contribution for my project work.

A Special thanks to the faculty of South Point College of Pharmacy, for their help and guidance
during the research.

I am very thankful to library In charge, for their help and guidance during the research.

I am thankful to my friends Sunny, Pawan, Himanshu for their constant support and
encouragement.

Words are inadequate to reflect the extent of my feeling for my parents whose bounteous
support, love, motivation, encouragement and sacrifice at various stages of my life has
provided the stepping stones for me to reach the milestone where I am today. My worthy
parents believed in me before I believed in myself.

ABHISHEK

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 INDEX

SR. NO TOPIC PAGE

NO.

1. INTRODUCTION 8-10

2. EPIDEMIOLOGY of ALZHEIMER’S DISEASE 10-12

3. COMMON SYMPTOMS of ALZHEIMER’DISEASE 12-13

4. ETIOLOGY of ALZHEIMER’S DISEASE 13-14

5. RISK FACTOR for ALZHEIMER’S DISEASE 14-18

6. PATHPHYSIOLOGY of ALZHEIMER’DISEASE 19-22

7. DIAGNOSIS of ALZHEIMER’S DISEASE 23-26

8. TREATMENT of ALZHEIMER’S DISEASE 26-32

9. POTENTIAL ROLE OF NANO PARTICLE IN TREATING OF 33-37

ACCUMULATION OF AMYLOID BETA IN ALZHEIMER’S
PATIENTS
A)POLYMERIC NANOPARTICLE EFFECT ON AMYLOID BETA
PEPTIDE
B) LIPID NANOPAFRTICLE EFFECT ON AMYLOID BETA
PEPTIDE
10. FUTURE ASPECTS 37-38

11. CONCLUSION 38-39

12. REFERNCES 39-50

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 LIST OF FIGURE

SR. NO DESCRIPTION PAGE NO.

1. The physiological structure of the brain and neurons in (a) 9

healthy brain and (b) Alzheimer’s disease (AD) brain

2. The risk factor for Alzheimer’s disease 18

3. Graphical representation of three primary pathophysiology 20

manifestations of Alzheimer’s disease

4. Diagrammatic representation of APP processing pathways 21

5. Diagram show the mechanism of neuronal cell death 22

6. Brain Scanning Images 25

7. Cholinesterase Inhibitors 28

8. Mechanism of Action of Memantine 30

9. Schematic Representation of potential pathway NP based drug 34

delivery system that penetrate the BBB for the treatment of
Alzheimer’s disease
10. The role of polymeric nanoparticles on the treatment 36
Alzheimer’s disease
11. Different types of lipid nanoparticles used in the treatment of 37
Alzheimer’s disease

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ABSTRACT

Alzheimer's disease (AD) is a progressive neurodegenerative disease. It is characterized by

progressive cognitive deterioration together with declining activities of daily living and
behavioral changes. It is the most common type of pre-senile and senile dementia. According
to the World Health Organization (WHO), 5% of men and 6% of woman of above the age of
60 years are affected with Alzheimer's type dementia worldwide. The clinical manifestation of
Alzheimer disease (AD) is dementia that typically begins with subtle and poorly recognized
failure of memory and slowly becomes more severe and, eventually, incapacitating. Currently
available treatments i.e. acetylcholinesterase inhibitors (rivastigmine, galantamine, donepezil)
and N-methyl d-aspartate receptor antagonist (memantine) contribute minimal impact on the
disease and target late aspects of the disease. These drugs decelerate the progression of the
disease, provide symptomatic relief but fail to achieve a definite cure. While the
neuropathological features of Alzheimer's disease are recognized but the intricacies of the
mechanism have not been clearly defined.

Owing to the important progress in the field of pathophysiology in the last couple of years,
new therapeutic targets are available that should render the underlying disease process to be
tackled directly. Understanding the extent of Alzheimer disease related knowledge can assist
disease management that result in improved disease management and reduced care costs. This
article attempts to focus on some of the important recent developments in understanding and
management of Alzheimer disease.

KEYWORDS: Alzheimer Disease, acetylcholine inhibitor, Diagnosis, Management

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1. INTRODUCTION

Alzheimer's disease (AD) is the most common cause of dementia and is clinically
characterized by a progression from episodic memory problems to a slow general decline of
cognitive function. [1] In 2013, ~44 million of the world-wide population was estimated to be
affected by dementia and a steep rise to ~136 million has been predicted by 2050 2. To date,
there are no treatments with proven disease-modifying effects and AD remains the largest
unmet medical need in neurology. [1] AD pathology presents a complex interplay between
several biochemical alterations, including changes in amyloid precursor protein metabolism,
phosphorylation of the tau protein, oxidative stress, impaired energetics, mitochondrial
dysfunction, inflammation, membrane lipid dysregulation and neurotransmitter pathway
disruption.[3] Most of these pathological features can be directly linked to metabolic
abnormalities and it is now clear that metabolic dysfunction is an important factor in AD.[4]
For example, impaired cerebral glucose uptake occurs decades prior to the onset of cognitive
dysfunction and is an invariant feature of AD.[5]

Figure-1. The physiological structure of the brain and neurons in (a) healthy brain and (b)
Alzheimer’s disease (AD) brain

The well-documented neurotoxicity associated with Aβ42 is thought to participate in impaired

neuronal energetics through initiating a cascade of pathological events; interaction between

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Aβ42 and mitochondrial enzymes leads to increased release of reactive oxygen species (ROS),
affecting glycolysis, the TCA cycle and mitochondrial respiratory-chain activity through the
accumulation of deleterious intermediate metabolites in the mitochondria.[6-7 ]

1.1Dementia

Dementia is a syndrome characterized by disturbance of multiple brain functions, including

memory, thinking, orientation, comprehension, calculation, learning capacity, language, and
www.wjpps.com Vol 5, Issue 6, 2016. 653 Muazzam et al. World Journal of Pharmacy and
Pharmaceutical Sciences judgment. Consciousness is not clouded. The impairments of
cognitive function are commonly accompanied, and occasionally preceded, by deterioration in
emotional control, social behavior, or motivation. [8-9] Dementia can affect a person in
different ways, and progression of the disease depends upon the impact of the disease itself and
the person’s personality and state of health. Dementia can be divided in three stages:

(A) early stage – first year or two

(B) middle stage – second to fourth or fifth years
(C) late stage – fifth year and after

2.EPIDEMIOLOGY OF ALZHEIMER’DISEASE

AD is a critical public health issue in the United States and many other countries around the
world, with a significant health, social, and financial burden on society. An estimated 5 million
Americans have AD, with a new diagnosis being made every 68 sec.8 In the United States, AD
is the fifth leading cause of death among older adults, and about $200 billion are spent annually
on direct care of individuals living with dementia. Worldwide, it is estimated that 35 million
people have AD or other types of dementia, and about 65 million people are expected to have
dementia by 2030 (115 million by 2050).

AD is a multi-factorial disease, with no single cause known, and several modifiable and
nonmodifiable risk factors are associated with its development and progression. Age is the
greatest risk factor for the development of AD. The likelihood of developing AD increases
exponentially with age, approximately doubling every 5 years after age 65. [10-11] The vast
majority ofindividuals suffering from AD are aged 65 or older andhave ‘late-onset’ or

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‘sporadic’ AD (95% of all cases).Rare genetic mutations are associated with the developmentof
AD before age 65, which is known as ‘earlyonset’or ‘familial’ AD (B5% of all cases). [12]
People with familial forms of AD have an autosomal dominant mutation in either one of the
presenilin genes located on chromosomes 1 and 14 or in the amyloid precursor protein (APP)
gene located on chromosome 21

. In addition, individuals with Down’s syndrome (trisomy 21) have an increased risk of
developing early-onset AD. The genetics of sporadic AD are more complex and less well
understood. It is known that the epsilon four allele of the apolipoprotein E (APOE) gene located
on chromosome 19 is a risk factor for the development of sporadic AD. [13] The prevalence of
AD is higher among females, reflecting the longer life expectancy of women. [14] Lower
educational attainment has been associated with increased risk of AD dementia,10 consistent
with the idea that education serves to increase a person’s cognitive reserve and resilience to
AD pathology. [15] A large body of evidence suggests that cerebrovascular risk factors play a
significant role in both the development progression of AD; people with a history of diabetes,
hypertension, obesity, and smoking have a substantially elevated risk of AD. [16] Family
history of AD in first-degree relatives and a history of head injury with loss of consciousness
are also risk factors for the development of A.[17]

2.1 History - Alois Alzheimer and Auguste D The German psychiatrist and neuropathologist
Dr Alois Alzheimer is credited with describing for the first time a dementing condition which
later became known as AD. In his landmark 1906 conference lecture and a subsequent 1907
article, Alzheimer described the case of Auguste D, a 51-year-old woman with a ‘peculiar
disease of the cerebral cortex,’ who had presented with progressive memory and language
impairment, disorientation, behavioural symptoms (hallucinations, delusions, paranoia), and
psychosocial impairment. [18-20]

The First Use of "Alzheimer's Disease"

Alzheimer later published his descriptions of several similar patients in 1909 and Kraepelin
included Ms. Deter's case in the 1910 edition of his widely respected psychiatry textbook. It
was Kraepelin who named this dementia after his junior colleague.

Auguste Deter was not an elderly woman at the onset of her illness, and Alzheimer's disease
(AD) was therefore regarded as a "presenile dementia" to distinguish it from the familiar "senile
dementia" thought to result from aging-related vascular disease. Further investigation,

11
however, showed that plaques and tangles were present in the brains of the majority of older
adults with symptoms of dementia.

In the late 1960's, the British psychiatrists Tomlinson and Roth described the importance of
these plaques in older adults, and in 1970 Dr.. Roth questioned the meaningfulness of the age
criterion that distinguished AD from "senile dementia of the Alzheimer's type."

(3) Table NO. 1: Common symptoms experienced by people with dementia

syndrome[21]

Early Stage Middle Stage Last Stage

The early stage is often The last stage is one of nearly
overlooked. Relatives and total dependence and
friends (and sometimes inactivity. Memory
professionals as well) see it As the disease progresses, disturbances are very serious
as "old age", just a normal limitations become clearer and the physical side of the
part of ageing process. and more restricting.
Become forgetful, especially Become very forgetful, Usually unaware of time and
regarding things that just especially of recent events place
happened and people's names
May have some difficulty Have difficulty Have difficulty
with communication, such as comprehending time, date, understanding what is
difficulty in finding words place and events; may happening around them
become lost at home as well
as in the community
Have difficulty making Unable to successfully Increasing need for assisted
decisions and handling prepare food, cook, clean or self-care (bathing and
personal finances shop toileting)
Mood and behaviour: may Unable to live alone safely May have bladder and bowel
become less active and without considerable support incontinence
motivated and lose
Interest in in activities and
hobbies may show mood

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 changes, including
depression or anxiety may
react unusually angrily or
aggressively on occasion.
Behaviour changes may Change in mobility, may be
include wandering, repeated unable to walk or be confined
questioning, calling out, to a wheelchair or bed
clinging, disturbed sleeping,
hallucinations (seeing or
hearing things which are not
there)
May display inappropriate Behaviour changes, may
behaviour in the home or in escalate and include
the community (e.g. aggression towards carer,
disinhibition, aggression). nonverbal agitation (kicking,
hitting, screaming or
moaning)
Source: World Alzheimer’s Report 2009. [22]

4.ETILOGY of Alzheimer’s Disease-

Researchers believe that many risk factors play a role in causing Alzheimer's and other
dementias, including genetics, behaviors and habits. While some risk factors, such as age and
family history, may be set in their influence, there are many risk factors that can be changed to
potentially reduce a person's risk of cognitive decline[23]

1.Age 2. Head Injury

3. Family History 4. Certain Medical condition

5. Genetics (heredity)

4.1.Age

The greatest known risk factor for Alzheimer’s and other dementias is increasing age, but these
disorders are not a normal part of aging. While age increases risk, it is not a direct cause of

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Alzheimer's.
Most individuals with the disease are 65 and older. After age 65, the risk of Alzheimer's doubles
every five years. After age 85, the risk reaches nearly one-third. [24-25]

4.2. Family history

Another strong risk factor for Alzheimer's is family history. According to research, those who
have a parent, brother or sister with Alzheimer’s are more likely to develop the disease. The
risk increases if more than one family member has the illness. Modifiable risk factors such as
sleep, smoking habits, hypertension or diabetes can further increase the risk.

4.3. Genetics (heredity)

Scientists know genes are involved in Alzheimer’s. Two categories of genes influence whether
a person develops a disease: risk genes and deterministic genes. Alzheimer's genes have been
found in both categories. It is estimated that less than 1% of Alzheimer’s cases are caused by
deterministic genes (genes that cause a disease, rather than increase the risk of developing a
disease).

4.4.Head Injury

There is a link between head injury and future risk of dementia. Protect your brain by buckling
your seat belt, wearing your helmet when participating in sports, and “fall-proofing” your home

4.5. Certain Medical condition

Some of the strongest evidence links brain health to heart health. This connection makes sense,
because the brain is nourished by one of the body’s richest networks of blood vessels, and the
heart is responsible for pumping blood through these blood vessels to the brain.

The risk of developing dementia appears to be increased by many conditions that also are not
good for our hearts, including high blood pressure and diabetes. Work with your doctor to
monitor your heart health and treat any problems that arise [26].

5 .Risk factor of Alzheimer’s disease-

5.1.1. Aging

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The most important risk factor in AD is aging. Younger individuals rarely have this disease,
and most AD cases have a late onset that starts after 65 years of age [27]. Aging is a complex
and irreversible process that occurs through multiple organs and cell systems with a reduction
in the brain volume and weight, a loss of synapses, and ventricles’ enlargement in specific areas
accompanied by SP deposition and NFT. Moreover, several conditions might emerge during
aging such as glucose hypometabolism, cholesterol dyshomeostasis, mitochondria dysfunction,
depression, and cognitive decline. These changes also appear in normal aging, which makes it
difficult to distinguish the cases in early AD [28-29]. AD can be divided based on age of onset
into early-onset AD (EOAD), the rare form with around 1–6% of cases, in which most of them
are familial AD characterized by having more than one member in more than one generation
with AD, and ranges from 30–60 or 65 years. The second type is the late-onset AD (LOAD),
which is more common with age of onset above 65 years. Both types may occur in people who
have a family with a positive history of AD and families with a late-onset disease [30].

5.1.2. Genetics

Genetic factors were discovered over the years and were found to play a major role in the
development of AD. 70% of the AD cases were related to genetic factors: most cases of EOAD
are inherited in an autosomal dominant pattern and mutations in the dominant genes such as
Amyloid precursor protein (APP), Presenilin-1 (PSEN-1), Presenilin-2 (PSEN-2), and
apolipoprotein E (ApoE) are associated with AD [31-32]. Herein, we discuss the strong genetic
risk factors in AD.

• Amyloid Precursor Protein (APP)

APP is a type I transmembrane protein cleaved by α-, β-, and γ-secretase to release Aβ and
other proteins and is encoded by the APP gene on chromosome 21. Thirty mutations have been
found in the APP gene in which twenty-five of them are related to AD and cause an
accumulation of Aβ with elevated amounts. Meanwhile, there is one protective mutation,
A673T, which protects Molecules 2020, 25, 5789 7 of 28 against AD by decreasing Aβ, Aβ40,
and Aβ42 secretion [33-34]. All mutations surround the secretase cleavage site, for example,
the KM670/671NL mutation in mouse models has shown an increasing level of amyloid
plaques in the hippocampus and cortex with no NFTs. A673V, D678H, D678N, E682K, and
K687N mutations have shown cortical atrophy, whereas E682K has shown hippocampal
atrophy. Neuropathological reports for the A673V mutation demonstrated a presence of NFTs
and Aβ, activation of microglia and astrocytes, and neuronal loss, compared to the rest of the

15
mentioned mutations, which show no change in the intracellular Aβ according to
neuropathological reports [33,35]. Other mutations such as T714I, V715A, V715M, V717I,
V717L, L723P, K724N, and I716V affect the γ-secretase cleavage site and cause an increase
in the Aβ42/Aβ40 ratio, while E693G, E693K, D694N, and A692G mutations affect the α-
secretase cleavage site and cause polymorphic aggregates with the ability to disrupt bilayer
integrity. Also, the E693delta is a deletion mutation that enhances the formation of synaptotoxic
Aβ [36-37].

• Apolipoprotein E (ApoE)

ApoE protein is a glycoprotein expressed highly in the liver and brain astrocytes and some
microglia and serves as a receptor-mediated endocytosis ligand for lipoprotein particles like
cholesterol, which is essential for myelin production and normal brain function. The ApoE
gene located on chromosome 19 has three isoforms, ApoE2, ApoE3, and ApoE4, due to single-
nucleotide polymorphisms (SNPs) which cause changes in the coding sequence. The ApoEε4
allele is a strong risk factor for both EOAD and LOAD compared to ApoEε2 and ApoEε3
alleles that

are associated with a lower risk and protective effect, respectively [38]. ApoEε4 plays an
important role in Aβ deposition as a senile plaque and causes cerebral amyloid angiopathy
(CAA), which is known as a marker for AD [39]. ApoEε4 was also shown to be associated with
vascular damage in the brain, which leads to AD pathogenesis [40].

• Other Genes

Other genes’ polymorphism associated with increasing the risk of AD include vitamin D
receptor (VDR) gene polymorphism, which affects the affinity of vitamin D to its receptor and
may cause neurodegenerative diseases and neuronal damage [41]. Moreover, epigenetic factors
like DNA methylation, histone, and chromatin modifications were demonstrated to be involved
in AD [42].

5.2.1.. Environmental Factors

Aging and genetic risk factors cannot explain all cases of AD. Environmental risk factors
including air pollution, diet, metals, infections, and many others may induce oxidative stress
and inflammation and increase the risk for developing AD. Herein, we report the most
important environmental factors and their relationships with AD [43-44]

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5.2.2. Air Pollution

The air pollution is characterized by modifying the nature of the atmosphere through the
introduction of chemical, physical, or biological pollutants. It is associated with respiratory and
cardiovascular diseases and recently, its association with AD was documented. Six air
pollutants have been defined by National Ambient Air Quality Standards (NAAQSs) in the
USA as a threat to human health, including ozone (O3), nitrogen oxides (NOx), carbon
monoxide (CO), particulate matter (PM), sulfur dioxide (SO2), and lead. Studies on animals
and cellular models have shown that an exposure to high levels of air pollution can result in a
damage to the olfactory mucosa and bulb, in addition to the frontal cortex region, similar to
that observed in AD. In individuals exposed to air pollutants, there is a link between oxidative
stress, neuroinflammation, and neurodegeneration, with the presence of hyper-phosphorylated
tau and Aβ plaques in the frontal cortex. The air pollution can cause an increase in Aβ42
formation, accumulation, and impaired cognitive function [45-46].

5.2.3. Diet

In recent years, the number of studies on the role of nutrition in AD have been increased.
Several dietary supplements such as antioxidants, vitamins, polyphenols, and fish were
reported to decrease the risk of AD, whereas

saturated fatty acids and high-calorie intake were associated with increasing the risk of AD
[47]. The food processing causes degradation of heat-sensitive micronutrients (e.g., vitamin C
and folates), loss of large amounts of water, and formation of toxic secondary products
(advanced glycation end products, AGEs) from non-enzymatic glycation of free amino groups
in proteins, lipids, and nucleic acids. The toxic effect of AGEs is referred to as their ability to
induce oxidative stress and inflammation by modifying the structure and function of the cell
surface receptors and body proteins.

5.2.4. Metals

Metals are found in nature and biological systems and can be divided into bio-metals that have
a physiological function in living organisms (e.g., copper, zinc, and iron), and toxicological
metals which do not possess any biological function (e.g., aluminium and lead) [48].
Aluminium is used significantly in the industries such as processed foods, cosmetics, medical
preparations, medicines, and others. In the body, aluminium is bound to plasma transferrin and
to citrate molecules that can mediate the transfer of aluminium to the brain. Studies

17
demonstrated that Al accumulates in the cortex, hippocampus, and cerebellum areas, where it
interacts with proteins and causes misfolding, aggregation, and phosphorylation of highly
phosphorylated proteins like tau protein, characteristic of AD []. Lead competes with the
binding site of bio-metals like calcium and can cross the blood–brain barrier (BBB) rapidly,
where it can modify neural differentiation and synaptogenesis and cause severe damage. [50]

5.2.5. Infections

Chronic infections to the central nervous system (CNS) can cause an accumulation of Aβ
plaques and NFT, therefore, they are included among the risk factors in AD. Studies by Dr.
Itzhaki showed that the DNA of herpes simplex virus (HSV-1) was found in patients with
ApoE-ε4 allele carriers, which explains the high risk for developing AD. HSV-1 can replicate
in the brain, which can result in the activation of the inflammatory response and an increase in
Aβ deposition, resulting in damage to neurons and gradual development of AD[51-53]

Figure.2- The Risk Factor For Alzheimer’s Disease

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6. Pathophysiology

Since its discovery and classification, the pathophysiology of Alzheimer’s disease has been
studied extensively, leading to confirmation of the two prominent neuropathological motifs that
Alois Alzheimer (54) and Oskar Fischer (55) first identified in the early 1900s: plaques and
neurofibrillary tangles (56). The first, senile plaques, are defined as extracellular aggregates of
beta-amyloid protein (Aβ), which is produced through proteolytic cleavage of a critical
membrane glycoprotein, amyloid precursor protein (APP) (57). While APP can
be differentially cleaved by β-secretase and γ-secretase to produce Aβ peptides of various
lengths, it is the 42 amino acid form that is predominantly involved in plaque formation (58),
as a result of its decreased solubility and increased propensity for fibril assembly. These fibrils,
while largely implicated in Aβ plaque formation, represent only one of the potential polymeric
forms of Aβ. Because a variety of studies have shown that Aβ plaque formation is not correlated
with the incidence or severity of Alzheimer’s (59), attention has largely turned to the oligomeric
form of Aβ, which is soluble and capable of spreading throughout the brain via the
cerebrospinal fluid (CSF) (60). These oligomers have the potential to bind to a number of
extracellular receptors (61), at least one of which (PrPC) is demonstrated to recognize and bind
Aβ fibrils and oligomers, preventing their elongation and contributing to the formation of short
and highly neurotoxic Aβ polymers (62). Upon binding, their cytotoxic effects seem to
be mediated by disrupted Ca2+ signaling, oxidative stress, and mitochondrial dysfunction
(63). Notably, a 2002 paper published in Nature showed that Aβ oligomers, in the absence of
monomers and fibrils, significantly inhibit long-term potentiation in the hippocampus of rats
(64). Many studies have attempted to determine the mechanism for this neuronal damage; for
example, a 2020 study found that incubation with soluble Aβ oligomers led to sensitization of
Toll-like Receptor 4 (TLR4) and increased production of Tumor Necrosis Factor-ɑ (TNF-ɑ) in
murine microglia and astrocytes (65). However, research into the role of Aβ in Alzheimer’s is
far from complete—in the light oF

news that data from a critical 2006 study demonstrating the role of 56kDa Aβ oligomers in
murine impairment (66) was likely falsified, new findings are of critical importance in
affirming the validity of existing research

19
FIGURE.3- Graphical representation of the three primary pathophysiological manifestations
of Alzheimer’s disease. (A) The amyloid plaque in the cerebral cortex is formed as a result of
APP cleavage to form the Amyloid-beta monomer, which can subsequently form soluble
oligomers. These oligomers can exert neurotoxic effects as they are, but may also assemble
into insoluble protofibrils and later fibrils, which compose the plaques. (B) Depicted within a
pyramidal neuron of the hippocampus, the neurofibrillary tangle (NFT) is localized to the cell
body and results from the hyperphosphorylation of tau protein, which aggregates into paired
helical filaments (PHFs). (C) Death of basal forebrain cholinergic neurons is a prominent
marker of Alzheimer’s disease.

The second widely recognized component of Alzheimer’s pathophysiology is the presence of

intracellular neurofibrillary tangles (NFTs) (4). The primary structural constituents of these
tangles, paired helical filaments (PHFs), and single filaments (SFs), have a common structural
origin and differ primarily in their aggregation pattern (67). These filaments result from the
entanglement of abnormally hyperphosphorylated tau protein (68); as this protein plays a
critical role in microtubule assembly and maintenance, its phosphorylation at certain

20
Serine/Threonine residues alters its chemical and physical properties such that it can no longer
fulfill its biological function (69). Specifically, it has been found that hyperphosphorylated tau
protein is unable to bind tubulin (which is critical for its role in microtubule assembly), but
readily binds to normal tau protein and other microtubule-associated proteins (70), contributing
to the loss of cytoskeletal microtubules (71) and increased intracellular tau aggregation
observed in the Alzheimer’s brain. Further, tau hyperphosphorylation contributes to
intracellular tau mislocalization, including to the dendritic spine where it contributes to
synaptic dysfunction (72). Further, the degeneration of cholinergic neurons in the nucleus
basalis has been widely documented in the brains of patients with Alzheimer’s (73), eliciting
an alternative, cholinergic hypothesis forthe cognitive deficits observed in AD

figure.4 -diagrammatic representation of APP processing pathways

21
 Amyloid ẞ precursor protein (APP)

ẞand y secretases

Amyloid ẞ peptide

Senile plaques + Neurofibrillary tangles

Accumulation on neurons

Neuron cell death

Neurotransmitter deficit

Impairment of cognitive function

FIGURE 5: Diagram shows the mechanism of neuronal cell death.

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7. Diagnosis of Alzheimer Disease-

There is no single test that can determine if a person is living with Alzheimer’s or another
dementia. Physicians use diagnostic tools combined with medical history and other
information, including neurological exams, cognitive and functional assessments, brain
imaging (MRI, CT, PET) and cerebrospinal fluid or blood tests to make an accurate
diagnosis.[74]

1. Medical history 2. Depression Screen

3. Physical exam and diagnostic test 4. Brain Imaging

5. Neurological exam 6. CSF Test

7. Blood Test 8. Cognitive ,functional test

1. Medical history

During the medical workup, the health care provider will review the person's medical
history, including psychiatric history and history of cognitive and behaviourl changes. He
or she will want to know about any current and past medical problems and concerns, as
well as any medications the person is taking. The doctor will also ask about key medical
conditions affecting other family members, including whether they may have had
Alzheimer's disease or other dementias.

2. Physical exam and diagnostic test

During a medical workup, the physician will likely:

• Ask about diet, nutrition and use of alcohol.

• Review all medications. (Bring a list or the containers of all medicines currently
being taken, including over-the-counter drugs and supplements.)

• Check blood pressure, temperature and pulse.

• Listen to the heart and lungs.

• Perform other procedures to assess overall health.

23
 • Collect blood or urine samples for laboratory testing.
Information from a physical exam and laboratory tests can help identify health issues
that can cause symptoms of dementia. [75]

3. Neurological Exam

During a neurological exam, the physician will closely evaluate the person for problems
that may signal brain disorders other than Alzheimer's. The doctor will look for signs of
stroke, Parkinson's disease, brain tumors, buildup of fluid in the brain, and other
conditions that may impair memory or thinking

The physician will test:

• Reflexes.

• Coordination, muscle tone and strength.

• Eye movement.

• Speech.

• Sensation.
4. cognitive ,functional and behavioural test

Cognitive, functional and behavioral tests evaluate memory, thinking and simple
problem-solving abilities, and may quickly assess changes in behaviors and symptoms.
Some tests are brief, while others can be more time intensive and complex. More
comprehensive cognitive, functional and behavioral tests are often given by a
neuropsychologist to evaluate executive function, judgment, attention and language.

Such tests may give an overall sense of whether a person is experiencing cognitive
symptoms that affect activities of daily living and function and is aware of these
symptoms; knows the date, time and where he or she is; and can remember a short list of
words, follow instructions and perform simple calculations.[76]

5.Depression Screen

24
In addition to assessing mental status, the doctor will evaluate a person's sense of well-
being to detect depression or other mood disorders that can cause memory problems, loss
of interest in life, and other symptoms that can overlap with dementia.

6. Brain Imaging

A standard medical workup for Alzheimer's disease often includes structural

imaging with magnetic resonance imaging (MRI) or computed tomography (CT). These
tests are primarily used to rule out other conditions that may cause symptoms similar to
Alzheimer's but require different treatment. Structural imaging can reveal tumors,
evidence of small or large strokes, damage from severe head trauma, or a buildup of fluid
in the brain.[77]

6.1 Fluorodeoxyglucose (FDG) PET imaging scans show areas of the brain in which
nutrients are poorly metabolized. Finding patterns in the areas of low metabolism can help
distinguish between Alzheimer's disease and other types of dementia.

Figure.-6 Brain Scanning images

25
6.2 Amyloid PET imaging can measure the burden of amyloid deposits in the brain. This
test is mainly used in research but may be used if a person has unusual or very early onset of
dementia symptoms.
6.3 Tau PET imaging, which measures the tangles in the brain, is generally used in the
research setting.

7. CSF test

CSF is a clear fluid that bathes and cushions the brain and spinal cord. Adults have about
1 pint of CSF, which physicians can sample through a minimally invasive procedure
called a lumbar puncture, or spinal tap. Research suggests that Alzheimer's disease in
early stages may cause changes in CSF levels of multiple markers such as tau and beta-
amyloid, two markers that form abnormal brain deposits strongly linked to Alzheimer's.
Another potential marker is neurofilament light (NfL), an increased level of which has
been found in neurodegenerative diseases such as Alzheimer’s.
There are a few new CSF tests — Lumipulse® and Elecsys® — that have received FDA
approval. These diagnostic tools can be used by clinicians to detect beta-amyloid and tau
markers in CSF, which can be predictive of amyloid changes in the brain.[77]

8. Blood test

Researchers are investigating whether consistent and measurable changes in blood levels
of specific markers may be reliably associated with Alzheimer’s related changes. These
markers may include tau, beta-amyloid or other biomarkers the could be measured
before and after symptoms appear.
An urgent need exists for simple, inexpensive, non-invasive and easily available diagnostic
tools such as blood tests to diagnose the disease. These testing technologies would support
drug development by helping to identify and follow treatment effectiveness in clinical trial
participants and to increase the possibility of early detection, diagnosis and intervention.
A blood test would also enable interpretation and understanding of the progression of
Alzheimer’s in larger and more diverse populations.[78]

8 .TREATMENT OF ALZHEIMER DISEASE-

Currently, Alzheimer’s disease cases worldwide are reported to be around 24 million, and in
2050, the total number of people with dementia is estimated to increase 4 times. Even though

26
AD is a public health issue, as of now, there is only two classes of drugs approved to treat AD,
including inhibitors to cholinesterase enzyme (naturally derived, synthetic and hybrid
analogues) and antagonists to N-methyl d-aspartate (NMDA). Several physiological processes
in AD destroy Ach-producing cells which reduce cholinergic transmission through the brain.
Acetylcholinesterase inhibitors (AChEIs), which are classified as reversible, irreversible, and
pseudo-reversible, act by blocking cholinesterase enzymes (AChE and butyrylcholinesterase
(BChE)) from breaking down ACh, which results in increasing ACh levels in the synaptic cleft
. On the other hand, overactivation of NMDAR leads to increasing levels of influxed Ca2+,
which promotes cell death and synaptic dysfunction. NMDAR antagonist prevents
overactivation of NMDAR glutamate receptor and hence, Ca2+ influx, and restores its normal
activity. Despite the therapeutic effect of these two classes, they are effective only in treating
the symptoms of AD, but do not cure or prevent the disease .

8.1. Symptomatic Treatment of AD

8.1.1. Cholinesterase Inhibitors

According to the cholinergic hypothesis, AD is due to the reduction in acetylcholine (ACh)

biosynthesis. Increasing cholinergic levels by inhibiting acetylcholinesterase (AChE) is
considered one of the therapeutic strategies that increases cognitive and neural cell function.
AChEIs are used to inhibit acetylcholine degradation in the synapses, which results in
continuous accumulation of ACh and activation of cholinergic receptors. Tacrine
(tetrahydroaminoacridine) (1, Figure 4) was the first FDA (Food and Drug Administration)-
approved cholinesterase inhibitor drug for the treatment of AD, which acts by increasing ACh
in muscarinic neurons, but it exited the market immediately after its introduction due to a high
incidence of side effects like hepatotoxicity and a lack of benefits, which was observed in
several trials. Later on, several AChEIs were introduced, such as donepezil (2, Figure 4),
rivastigmine (3, Figure 4), and galantamine (4, Figure 4), and are currently in use for the
symptomatic treatment of AD [34,97,102,103]. Another strategy that may help in the treatment
of AD is increasing choline reuptake and as a result, increasing acetylcholine synthesis at the
presynaptic terminals. This can be achieved by targeting choline transporter (CHT1) which is
responsible for supplying choline for the synthesis of ACh. Developing drugs that are capable
of increasing CHT1 at the plasma membrane may become the future therapy of AD [36]

27
 FIGURE.7-Cholinesterase inhibitors

(A) Donepezil

Donepezil (2, Figure 7) is an indanonebenzyl piperidine derivative and a second generation

of AChEIs and is considered the leading drug for AD treatment. Donepezil binds to
acetylcholinesterase reversibly and inhibits acetylcholine hydrolysis, which leads to a higher
concentration of ACh at the synapses. The drug is well-tolerated with mild and transient
cholinergic side effects which are related to the gastrointestinal and nervous systems. It should
be noted that donepezil is used to treat symptoms of AD such as improving cognition and
behavior without altering the AD progression [79-82].

(B) Rivastigmine

Rivastigmine (3, Figure 4) is a pseudo irreversible inhibitor of AChE and butyrylcholinesterase

(BuChE) that acts by binding to the two active sites of AChE (anionic and estearic sites), which
results in preventing ACh metabolism. BuChE is found mostly in glial cells with only 10% of
AChE activity in the normal brain, whereas in the AD brain, its activity is increased to 40–
90%, while ACh activity is reduced simultaneously, which suggests that BuChE action may
indicate a moderate to severe dementia. Rivastigmine dissociates more slowly than AChE,
which is why it is called a pseudo-irreversible, and it undergoes metabolism at the synapse by
AChE and BuChE. The drug is used in m ild to moderate AD cases. It improves cognitive

28
functions and daily life activities. Oral administration of the drug is associated with adverse
effects such as nausea, vomiting, dyspepsia, asthenia, anorexia, and weight loss. In many cases,
these they can be settled down in time and consequently, the drug becomes more tolerated.
Rivastigmine can be delivered by transdermal patches for controlled and continuous delivery
of the drug through the skin, with enhanced tolerability and caregiver satisfaction. Also, the
patches can deliver a lower dosage compared to pills, which results in reduced side effects.
Most AD patients suffer from memory loss and swallowing problems which affect their
compliance in administering oral drugs at regular intervals. Therefore, the use of transdermal
patches is the most appropriate method for delivering the drug in AD patients [83-87]

(C )Galantamine (GAL)

Galantamine is considered a standard first-line drug for mild to moderate AD cases. GAL is a
selective tertiary isoquinoline alkaloid with a dual mechanism of action in which it acts as a
competitive inhibitor of AChE and can bind allosterically to the α-subunit of nicotinic
acetylcholine receptors and activate them. GAL can improve behavioral symptoms, daily life
activities, and cognitive performance with good efficacy and tolerability, similar to other AChE
inhibitors. Several delivery systems were developed to improve the drug delivery to the brain:
Wahba et al. attached GAL to ceria-containing hydroxyapatite particles for selective delivery
of the drug to the affected regions in the brain. Misra et al. and Fornaguera et al. used solid-
lipid nanoparticles and nano-emulsification approaches respectively, to carry GAL
hydrobromide. The results of these studies demonstrated a promising strategy for safe delivery
of the drug. Hanafy et al. developed nasal GAL hydrobromide/chitosan complex nanoparticles
which showed good pharmacological efficacy, while Woo et al. utilized the patch system as a
carrier for a controlled release dosage form of the drug [87-91]

8.2. N-methyl d-aspartate (NMDA) Antagonists

NMDAR is believed to have a dominant role in the pathophysiology of AD. NMDAR

stimulation results in Ca2+ influx which activates signal transduction and as a consequence, it
triggers gene transcription essential for the formation of a long-term potentiation (LTP), which
is important for synaptic neurotransmission, plasticity, and memory formation. Over-activation
of NMDARs causes an abnormal level of Ca2+ signaling and overstimulation of glutamate,
which is the primary excitatory amino acid in the CNS, which results in excitotoxicity, synaptic

29
dysfunction, neuronal cell death, and a decline in cognitive functions. Several NMDAR
uncompetitive antagonists have been developed and entered clinical trials, however, most of
them failed due to low efficacy and side effects. Memantine (5, Figure 4) is the only approved
drug in this category to treat moderate to severe AD; in addition, other NMDAR uncompetitive
antagonist compounds are being developed, such as RL-208 (3,4,8,9-tetramethyltetracyclo
[4.4.0.03,9.04,8]dec-1-yl)methylamine hydrochloride), a polycyclic amine compound that may
possess a promising therapeutic effect in age-related cognitive problems and AD [93-94].

(A) Memantine - Memantine is a low-affinity uncompetitive antagonist of the NMDAR, a

subtype of glutamate receptor that prevents over-activation of the glutaminergic system
involved in the neurotoxicity in AD cases. Memantine is used for the treatment of moderate to
severe AD alone or in combination with AChEI. The drug is safe and well-tolerated, it blocks
the excitatory receptor without interfering with the normal synaptic transmission due to
memantine’s low affinity, where it is displaced rapidly from NMDAR by high concentrations
of glutamate, thus avoiding a prolonged blockage. The latter is associated with high side
effects, especially on learning and memory [95]

Figure.8-Mechanism of Action of Memantine

30
31
[96-98]

32
9. Potential Role of Nanoparticles in Treating the Accumulation of Amyloid-
Beta Peptide in Alzheimer’s Patients-

The treatment of AD includes hundreds of smaller molecular inhibitors. The blood–brain

barrier (BBB) [99] cannot in any way block all these medicines. The blood–brain barrier does
not exist. Nerve cells in the brain neurons are expected to accumulate Aβ peptides in
Alzheimer’s disease and to lead to progressive memory loss. There are signs of initiation and
development of AD because of Aβ changes, especially the generation of neurotoxic oligomers
10–20 years before deficiency [100]. The functional cognitive disorder may also occur well
before the disease begins if Aβ is produced and cholinergic systems dislocate. Nanoparticles
combine the targets, visualization, and treatment in one form to give drug molecules new hope
and cross BBB[101]. shows the effects of different types of nanoparticles on the treatment of
Alzheimer’s.

Because the BBB level with nanoparticles is difficult to cross, particles will cross the BBB
within the 50–100 nm range without complex adaptation. If there is a limit to the crossing of
the BBB [102], a therapeutic solution is recommended for each nanoparticle derivative. The
extra iron dramatically accelerates AD in the brain, and the cells are destroyed by excess iron.
On AD plates and in situ-considered encounters because of pathological iron dysfunction,
magnet nanoparticles able to catalyze the formation of reactive oxygen species [103] are
present. To avoid and minimize the growth of Aß, combination therapy is required to
simultaneously manage the imbalance of acetylcholine as a potential cure for AD. Clioquinol
(metal-ion chelating agent) and donepezil (acetylcholinesterase (AChE) inhibitor) co-
encapsulated human serum albumin (HSA) nanoparticles (dcHGT NPs) [104]. A central
limiting factor in brain supply is the BBB. The intention was not to concentrate on
pharmaceuticals using traditional medicinal products. The most promising mechanism in the
delivery of nasal drugs was an improvement in brain medicine [105]. Pharmaceutical products
availability. Lower solubility, low blood–brain barrier and low dryness of anti-AD products
decrease therapeutic efficacy.

In this connection, large and small molecular medicine for the treatment of AD seems to be
promising. Nasal supplies are a popular road. This promising trip results in bad neighborhood
systemic results, greater bioavailability, and therapeutic efficacy [106] on the olfactory route

33
to the brain. The primary Aβ fibrillation engine is the Lys-Leu-Val-Phe-Phe (KLVFF) series.
Aβ is also used for attack, and Aβ aggregation can be avoided [107]. Based on significant
nanoscience and nanotechnology advancement, biosensor advances have made significant
progress in recognizing essential AD biomarkers. The special and special features of
nanomaterials improve the electrochemical and optical activity of the transducer to immobilize
biological components of detection [108]. The aim of this review is to shed light on the use of
nanotechnology in treating Alzheimer’s disease using nanoparticles. To clarify the effective
role of these nanoparticles, they were divided into three sections, and they are polymeric, lipid
and gold nanoparticles. The next sections will deal with more details about them. A comparison
is made between the characteristics of each and the volumes used in each of the treatment
methodologies

Figure.9- Schematic representation of potential pathway NP based drug delivery systems

that penetrate the BBB for the treatment of Alzheimer’s disease

9.1 Polymeric Nanoparticles Effects on Amyloid Beta Peptide

Diseases to cure multiple diseases and to resolve treatment hurdles promise to be treated easily
with multifunction. The main enzyme in Aβ formation has been reduced by the supply of non-

34
coding plasmid ribonucleic acid (RNA). Concurrent delivery of therapeutic peptides to the
brain helps to reduce neurofibrillary entanglements [109]. It has been extensively explored on
the routes of nano-sufficiency, such as liposomes, polymeric nanoparticles, micelles,
conjugates, peptide carriers, cyclodextrins, stable dispersions, lipid nanoparticles, and
emulsions. The effect of molybdenum disulfide inhibition is known as molybdenum disulfide
(MoS2). A laser-pulsed removal method was used in polyvinylpyrrolidone functional MoS2
NPs.

In Aβ aggregation inhibitors, Aß destabilization, oxidative stress relaxation caused by Aβ and

cell toxicity, multifunctional effects have been observed. Initially, MoS2 NPs obstructed the
production of cell membrane channels [110] triggered by Aβ-fibrillation. In addition to nerve
growth factor (NGF), release and disease modification approaches to AD, the role of
nanoparticles in the brain, in genes, and in cell screening therapy from polymerized implants,
as a neuroprotector, was emphasized. Promising nanoparticles and quantum points, lipids, and
polymer-dependent delivery mechanisms have been investigated to achieve the present NGF
therapeutic weaknesses [111]. Deposits are disposed of to shield them from Aβ. While several
aggregation inhibitors have been studied, there are only limited NP ratios. NPs provide an ideal
environment for tunable Aβ-rational structure, surface, and size aggregation inhibitors. The
degree of aggregation was modified by the NP and surface chemistry, while the aggregate
morphology was determined by the electrical charge of the NP. The mixture of Aß was repealed
at 8 nm and 18 nm of poly-coated NPs (acrylic acid), with a sub-stoichiometric ratio of
1:2,000,000 [112]. Aβ 1-42 model tested the neuroprotective efficacy of anthocyanin-powered
nanoparticles polyethylene glycol-gold (PEG-AuNPs).

Using AuNPs@POMD-pep, the use of BBB to deal with drawbacks of small molecular anti-
AD medication [113] is being used to cross BBBs. Approved expression and successful
clearing in microglia and liver cells of the Aß low-density lipoprotein receptor (LDLR) α-
mangostin, which is in vivo is decreased due to hydrophobia, low solubility and aqueous
environ-mental stability, hence low bioavailability and objective aggregation of bacteria. PEG-
PLA was encapsulated to overcome this limitation. To overcome this limit, poly-metals were
encapsulated [114]

Alteration of poly-lactide-co-glycolides and selenium nanoparticles’ encapsulation in

Alzheimer’s disease therapy can improve bioactivity and drug delivery characteristics of

35
curcumin nanoformulation (Se NPs). It has been examined using analytical instrument
techniques to determine the moral structures of the polymer.

Figure.10-The role of polymeric nanoparticles on the treatment of AD.

9.2 Lipid Nanoparticles Effects on Amyloid Beta Peptide

Both metabolites given intravenously can be quickly metabolized in the liver and the intestine
into two dangerous metabolites. One easy way to remove toxins is by using combined subunits.
That is not like an antidepressant as the substance cannot pass through the blood–brain barrier.
The particles of surfactant were prepared by a double emulsion evaporation technique.
Glaucoma is a disease in which the patient’s vision slowly reduces over the course of days or
weeks, and it eventually goes completely. The two situations are often linked for many reasons.
The particles also help protect the nerve, and especially the brain, by promoting the delivery of
nanotechnology. Luca Technologies is one of the primary companies that master the field of
drug delivery. It is possible that the medicines that are causing the disorder are made stronger

36
through the help of nanoparticles [115]. The brain supply system Beta-Secretase 1 (BACE1)
with small interfering RNA (siRNA) is optimal and functional. A short peptide extract from
the chimeric rabies virus glycoprotein fragment (RVG-9R) glycoprotein virus enhances
transcellular trajectory in neuronal cells. The perfect molar relationship between siRNA and
BACE1 was thus demonstrated. The installation between them was screened. The nasal
delivery system was proposed for olfactory and trigeminal pathways. The coating process
affects the loading and protection of nanoparticles [116].

Figure.14-shows different types of lipid nanoparticles used in the treatment of AD.

Figure -11-Different types of lipid nanoparticles used in the treatment of AD

10. Future Aspect

The Alzheimer's Association is the world's largest nonprofit funder of Alzheimer's research.
Since 1982, we have awarded over $350 million to more than 2,300 research investigations
worldwide.

When Dr. Alois Alzheimer first described the disease in 1906, a person in the United States
lived, an average of about 50 years. Few people reached the age of greatest risk. As a result,
the disease was considered rare and attracted little scientific interest. That attitude changed
asthe average life span increased and scientists began to realize how often Alzheimer's strikes

37
people in their 70s and 80s. The Centers for Disease Control and Prevention recently estimated
the average life expectancy to be 78.8 years.

Today, Alzheimer's is at the forefront of biomedical research, with 90 percent of what we know
discovered in the last 20 years. Some of the most remarkable progress has shed light on how
Alzheimer's affects the brain. Better understanding of the disease's impact may lead to better
treatments.

(A) Clinical studies drive progress

Scientists are constantly working to advance our understanding of Alzheimer's. But without
clinical research and the help of human volunteers, we cannot treat, prevent or cure
Alzheimer's. Clinical trials test new interventions or drugs to prevent, detect or treat disease
for safety and effectiveness. Clinical studies are any type of clinical research involving. people
and those that look at other aspects of care, such as improving quality of life. Every clinicaltrial
or study contributes valuable knowledge, regardless if favorable results are achieved.

b) New directions in treatment and prevention

One promising target is beta-amyloid. This protein fragment builds up into the plaques
considered to be one hallmark of Alzheimer's disease. Researchers have developed several
ways to clear beta-amyloid from the brain or prevent it from clumping together into plaques.
Experimental drugs that zero in on beta-amyloid are now being tested. Many other new
approaches to treatment are also under investigation worldwide. We don't yet know which of
these strategies may work, but scientists say that with the necessary funding, the outlook is
good for developing treatments that slow or stop Alzheimer'.

. Eating a diet low in saturated fats and rich in fruits and vegetables, exercising regularly, and
staying mentally and socially active may all help protect the brain.

11. CONCLUSION

Alzheimer's disease is the most common form of dementia in older adults. The disease is
extremely complex, with causes not fully understood. Patients progress through degenerative,
irreversible phases of the disease, while cognitive functioning (memory, thinking and
reasoning) and behavioural abilities are affected, up to the point where the person must depend
completely on others for basic activities of daily living. Current pharmacological treatment
used in the management of AD may ease the symptoms for a period of time, but donot stop the

38
persistent downward progression of the disease. Patients may benefit from non-
pharmacological strategies tailored to the needs of the individual person. Ongoing research
indicated that specific precautionary measures, i.e., higher education and improved heart
health, are most likely to delay the onset of AD. The urgent need for drug development is
echoed by the words of Margaret Chan, the Director-General, World Health Organization "I
can think of no other disease where innovation, including breakthrough discoveries to developa
cure, is so badly needed."

As medical care becomes more complex and people live longer, the share of the population
over 60 continues to grow, and the incidence of Alzheimer's disease and other dementias
increases, many groups in society feel the effects and pressures. For the healthcare industry
there are pressures both financial- and personnel-related.

No doubt for healthcare providers it can be daunting to take on yet more responsibility but, in
the long term, improving support to caregivers of those with Alzheimer's and other dementias
(and to all family caregivers) stands to save everyone individuals, communities, state and
federal governments-time and money by reducing the need for emergency visits, hospital
readmissions, and related services, and improving the quality of life for care recipients,
caregivers, and all those who support them.

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