ZAGAZIG UNIVERSITY

Faculty of Science
Biochemistry and
Microbiology Department

Graduation project (2026)

Alzheimer’s Disease

Prepared by
Sama Ibrahim Atia Hussein

Under supervision
Dr./ Aml Nassr Mohammed
Lecturer of Biochemistry
 Content Page number
List of figures |
List of abbreviation ||
What’s Alzheimer’s disease? 1
1. Stages and Symptoms 2
2. Mechanisms of Alzheimer's Disease 4
2.1. Aβ Plaque Associated Neurodegeneration 4
2.2. Neuroinflammation 5
2.3. Infectious Disease Hypothesis 5
2.4. Genetic Mutations 6
2.5. Oxidative Stress 6
2.6. Autophagy 7
2.7. Neurofibrillary Degeneration 7
3. Diagnostics of Alzheimer's Diseases 8
4. Causes and Risk factors of Alzheimer's Disease 10
4.1. Alzheimer's Disease Hypotheses 12
4.2. Alzheimer’s Disease Risk Factors 14
5. Newer strategies in early detection of Alzheimer’s disease 22
5.1. Biomarkers 22
5.2. CerebroSpinal Fluid (CSF) Proteins 23
5.3. Genatic markers 24
5.4. Brain Imaging 25
6. Treatment 26
7. Current strategies in the treatment of Alzheimer’s disease 27
7.1. FDA approved medicines 28
7.2. Gene Therapy in Alzheimer’s Disease 28
7.3. Voice as Biomarkers using Artificial Intelligence 29
8. Ways to Lower your risk of dementia 30
9. Conclusion 33
10. References 34
 List of Figures

Figure Figure title Page

No
Figure 1 The physiological structure of the brain and neurons 1
Figure 2 the difference between a healthy brain and an injured brain 3
Figure 3 Compiles all the important mechanisms explored till now 8
Figure 4 The Risk factors for Alzheimer's Disease 11
Figure 5 The pathway for synthesis and transportation of acetylcholine 13
Figure 6 Mechanisms involved on pathogenesis of AD 29

I
Abbreviations Full name
AD Alzheimer's disease
Aβ Amyloid-beta
APP Amyloid precursor protein
PS1 Presenilin 1
PS2 Presenilin 2
APOE Apolipoprotein E
CRH Corticotrophin – releasing hormone
GSK-3 Glycogen synthase kinase
OS Oxidative stress
NMDARs N-Methyl-D-aspartate-type glutamate receptors
Rns Reactive nitrogen species
NADPH Nicotinamide adenine dinucleotide phosphate hydrogen
NFTs Neurofibrillary Tangles
MRI Magnetic resonance imaging
NINCDS NATIONAL Institute of Neurological and communicative
disorder and stroke
ADEDA Alzheimer’s disease and related disorders association
PET Positron emission tomography
CSF Cerebrospinal fluid
FDG fluorodeoxyglucose
ChAT Choline acetyltransferase
ACh Acetylcholine
EAA Excitatory amino acid
NBM Nucleus basalis of Meynert
VACht Vesicular Acetylcholine transporter
AP Amyloid plaque
NIAD Non-inherited of Alzheimer’s disease
IAD Inherited Alzheimer’s disease
EOAD Early onest Alzheimer disease
LOAD Late Onest Alzheimer Disease
ABCA1 ATP Binding Cassette Transporter A1
ATP Adenosine triphosphate
Apo AI Apolipoprotein AI
HDL High Density lipoprotein
VDR Vitamin D receptor

II
NAAQSs National Ambient air quality standards
CVDs Cardiovascular Disease
BMI Body mass index
IGT Impaired glucose tolerance
PET Positron emissions tomography
CRP C-reactive protein
FDG Fluro-deoxy glucose
DTI Diffusion tensor imaging
18F-FDG PET 18F- flourodeoxyglucose-positron emissions
tomography
NMDA N-methyl d-aspartate
AChEIs Acetylcholinesterase inhibitors
AChE Cholinesterase Enzymes
BChE Butyrylcholinesterase
MD Mediterranean diet
rAAVs Recombinant adeno-associated virus
NGF Nervous system growth factor
ES Early stage
IS Intermediate stage
AS Advanced stage

III
What’s Alzheimer Disease?
Alzheimer’s disease (AD) (named after the German psychiatric Alois
Alzheimer) is the most common type of dementia and can be defined as
a slowly progressive neurodegenerative disease characterized by neuritic
plaques and neurofibrillary tangles (Figure 1) as a result of amyloid-beta
peptide’s (Aβ) accumulation in the most affected area of the brain, the
medial temporal lobe and neocortical structure( 1). At present, there are
around 50 million AD patients worldwide and this number is projected to
double every 5 years and will increase to reach 152 million by 2050. AD
burden affects individuals, their families, and the economy, with
estimated global costs of US$1 trillion annually. At present, there is no
cure for Alzheimer’s disease, although there are available treatments that
just improve the symptoms.(2)

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

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

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 1. Stages
1.1.1. Intial Stage/Mild Stage
This stage is asymptomatic. The only symptoms that can be seen
are wandering, getting lost in thoughts and small behavioral
changes. But by this time the damage has already started.
1.1.2. Moderate Stage
This stage is also known as pre dementia phase because there is
mild cognitive impairment or mild neurological disorder. It can be
seen that in this stage there is damage in areas of brain controlling
sensory, reasoning, language and conscious thoughts. Memory loss
and confusion can also be seen in some cases in this stage.
1.1.3. Severe Stage
This stage has major neurocognitive disorder. There are major
changes in cognitive behavior. Tissue gets severely shrunk and the
neurons cannot communicate. Patients at this stage has major
dementias and sometimes hallucinations. Changes in brain occurs
way before there is a cognitive problem in a patient. This is the
preclinical stage in which we are not able to see any symptoms but
toxic changes in brain starts to occur. These toxic changes
gradually increases. They can be deposition of plaques or any other
protein deposition.
These problems start affecting our hippocampus, entorhinal
complex and other parts of brain that are essential in forming
memories and in intellectual thinking.
Slowly the neurons die and in the last stage the brain has
shrunken.(3)

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Figure 2 : the difference between a healthy brain and an injured brain
depending on the stage of injury

1.2 Symptoms
a) Mild cognitive impairment
b) Problems with smell
c) Difficulty in movements
d) Patient starts having visions
e) Forgetting conversations
f) Troubles in handling day to day activities
g) Low energy
h) Depression
i) Hallucination (4)

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2. Mechanisms of Alzheimer's Disease
2.1. Aβ Plaque Associated Neurodegeneration
According to this hypothesis, Aβ plaques are formed and get
deposited in different regions of the brain. These plaques are
recognised as foreign material by the brain initiating an
inflammatory and immune response by activating the microglia
and release of cytokines, which eventually lead to cell death and
neurodegeneration. The Aβ plaque comprises of Aβ peptides
obtained from amyloid precursor protein (APP) by the enzymatic
cleavage via secretases (α, β and γ) (5) . The primary step in the
generation of Aβ plaque is the cleavage of amyloid precursor
protein (APP) by β-secretase to produce a C-terminal membrane
attached with fragments of 89 or 99 amino acids. This β-secretase
includes BACE 1 (β-site APP cleaving enzyme), which is also
called Asp2 or memapsin2. APP is cleaved at β-sites Asp1 and
Glu11 by BACE 1. The C-terminal membrane-bound fragment of
99 amino acid residues is further cleaved by γ-secretase to
produce Aβ1-40 and Aβ1-42 isoforms. γ-secretase mainly include
presenilin 1 (PS1) or presenilin 2 (PS2). Aβ1-40 is the normal
soluble isoform, but if the cleavage pattern changes it may give
rise to Aβ1-42, which aggregates easily and forms the plaque due
to two additional amino acids isoleucine and alanine (6) .
This change in the cleavage pattern happens due to mutations in
the APP gene, presenelin 1, presenelin 2 genes or apolipoprotein
E (APOE4) gene. Apart from the genetic mutations, many
neuropeptides are likely to be involved in the formation of the
plaque for e.g. low levels of corticotrophin-

4
 releasing hormone (CRH), somatostatin and neuropeptide Y levels
whereas higher levels of Angiotensin II are likely to be involved in
either irregular cleavage of the APP or impaired removal of Aβ1-
42fragment (7).. Both Aβ and tau aggregates and cause impaired
synaptic plasticity and neuronal cell death (8)
However, there has been a lot of controversy over this hypothesis
and a recent report indicates that drugs that act to inhibit amyloid
plaque formation show no effect in reversing or halting the
cognitive decline. This suggests that either the hypothesis is
incorrect or the brain becomes refractory to treatment after a
certain time. Thus, one should focus on finding therapeutic
interventions that act on non-amyloid targets like tau proteins,
inflammation, oxidative stress, etc.(9)
[Link]
Neuro-inflation plays a central role in the pathogenesis of AD.
Acute inflammation has a protective role in defending against
brain injury such as the presence of Aβ plaque. However,
persistent activation of microglia makes them incapable of
removing the plaque, but their ability to release pro inflammatory
cytokines is retained, resulting in an imbalance between the pro
and anti-inflammatory cytokines. (10)
[Link] Disease Hypothesis
Aβ has been attributed to have antimicrobial properties. It has
been suggested that neurons infected by Spirochetes and other
pathogens like Chlamydia and HSV-1 have more of Aβ
deposition and NFTs. Thus, the persistent untreated infection
could be one of the causes of AD (11) In the presence of
infection, the immune system gets activated. A component

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 of the innate immune system referred to as “Toll like proteins”
as mentioned above, is activated due to it (12)
[Link] Mutations
APOE gene has been closely related to the incidence of AD in most
cases (13) . Other genes involved are presenilin 1, presenelin 2
and mutations in β amyloid precursor protein
(14) . Due to mutations in the genes mentioned above, the person
becomes susceptible to AD.
2.5. Oxidative stress
Mitochondrial dysfunction and oxidative stress have long been
implicated in the pathogenesis of early AD. Decreased level of
cytochrome c oxidase can cause dysfunction of mitochondria.
Additionally, hyper excitation of glycogen synthase kinase (GSK-
3) due to oxidative stress (OS) can alter the permeability of
mitochondria. This could lead to overproduction of ROS (15) .
Metal ions specifically zinc and copper may bind to the Aβ plaque
and produce ROS. ROS thus produced brings about oxidative
change in the Aβ peptide itself making its removal difficult and also
cause lipid and protein oxidation of the cell membrane making it
permeable and hence susceptible to degeneration (16) . Calcium
ions storage in the endoplasmic reticulum can be impaired by Aβ
plaque, which increases calcium levels in the cytosol. This increase
in calcium levels depletes glutathione and over- accumulation of
ROS inside the cells. Hyperactivation of N- Methyl-D-aspartate-
type glutamate receptors (NMDARs) can also lead to increase
calcium influx by promoting cell permeability, which leads to the
formation of reactive nitrogen species (RNS) and ROS. Aβ
proteins can directly activate

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 nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)
oxidase to initiate the synthesis of free radicals (17)
[Link]
It is known as a housekeeping system or the waste management
system of the cell. It involves engulfing of the damaged proteins or
cell constituents. Nucleation is the first step in this process by
which a phagophore is formed. Then the phagophore extends to
enclose all the damaged proteins or the dysfunctional organelles.
This leads to formation of closed vacuoles known as
Autophagosomes. Finally, the autophagosomes fuse with
lysosomes to form autolysosomes which degrade all its contents.
Various growing factors for AD like presenelin 1 proteins, oxidative
stress, tau neurofibrillary tangles can cause dysfunction of
autophagic vacuoles and hence can contribute in the pathogenesis
of AD (18)
2.7. Neurofibrillary Degeneration
Tau proteins are micro tubular neuronal proteins. The tau proteins
have a microtubule binding domain, which is involved in
polymerization and stabilization of the microtubule assembly to
maintain the integrity of the cytoskeleton. This binding is regulated
by phosphorylation of the serine/ threonine residues by a variety of
kinases like Fyn Kinase,
Hyper phosphorylation results in decreased affinity of the tau
proteins to microtubules. The hyper phosphorylated tau forms NFTs
and gets deposited in the cytosol and can no longer perform the
function of maintaining the structure of the cell. Moreover, this
deposition affects normal cellular function like synaptic
transmission, axonal transport, signal transduction

7
 and the cell undergo degeneration gradually. The reason stated
for the hyper phosphorylation is a mutation in the tau genes
or dysregulation of kinases as mentioned below and
phosphatases which catalyze the phosphorylation
process (19) .

Figure 3 compiles all the important mechanisms explored till now,

which contributes towards having an understanding of the cause of
the disease.

3. Diagnostics of Alzheimer's Disease

A patient suspected to have AD should undergo several tests,

including neurological examination, magnetic resonance imaging
(MRI) for neurons, laboratory examinations such as vitamin B12,
and other tests besides the medical and family history of the
patients (20) . Vitamin (vit.) B12 deficiency has been long known
for its association with neurologic problems and increasing risks of

8
AD, according to some studies. A special marker of vit. B12
deficiency is elevated homocysteine levels, which can cause brain
damage by oxidative stress, increasing calcium influx and apoptosis.
Diagnoses of vit. B12 deficiency can be done by measuring serum
vit. B12 level alongside complete blood count and serum
homocysteine levels tests (21). In 1984, The National Institute of
Neurological and Communicative Disorders and Stroke (NINCDS)
and the Alzheimer’s Disease and Related Disorders Association
(ADRDA) formed a work group (NINCDS-ADRDA) to establish a
clinical diagnostic’s criteria for Alzheimer’s disease. This criteria
includes:
1. probable Alzheimer’s disease, which can be diagnosed by
dementia that is confirmed by neuropsychological tests,
progressive memory loss, impaired daily-life activity, and
other symptoms like aphasia (impairment of a language),
apraxia (a motor skills disorder), and agnosia (a loss of
perception). All of these symptoms can start from age 40–90,
with the absence of any systemic or brain diseases.
2. possible Alzheimer’s disease can be applied in the absence of
neurologic, psychiatric disorders, and the presence of another
illness like systemic or brain disorder, but they are not the
primary cause of dementia.
3. definite Alzheimer’s disease, that is confirmed by
histopathologic confirmation obtained from a biopsy or
autopsy (22).

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In 2011, The National Institute on Aging—Alzheimer’s
Association made several changes and updated the 1984
NINCDS-ADRDA criteria for higher specificity and sensitivity
in the diagnosis of Alzheimer’s disease. The newly proposed
criteria include probable and possible AD dementia for the use
in clinical settings and probable or possible AD dementia with
pathophysiological evidence for research purposes, in addition
to clinical biomarkers. There are two categories of Alzheimer’s
disease biomarkers:
a) markers of brain amyloid such as positron emission
tomography (PET) and cerebrospinal fluid (CSF)
b) markers of neuronal injury like cerebrospinal fluid tau,
fluorodeoxyglucose (FDG) for metabolic activity, and
magnetic resonance imaging (MRI) for atrophy measurement
(23).
4. Causes and Risk factors of Alzheimer Disease

Alzheimer's disease is caused by progressive neuronal

degradation short -term memory is affected first as
neurons in the hippocampus degenerate , and the
disease then gradually spreads to the entire brain .

The degradation is caused by changes to two

molecules :

1. Amyloid- Beta peptide : an abnormal

accumulation of amyloid beta

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 peptide,which occurs naturally in the brain Results in amyloid plaques
(also known as senile plaques) . This build-up is toxic for nerve cells in
Alzheimer's patients
2. Tau protein : tau normally helps maintain neuron structure , but in
alzheimer's patients it altered , disrupting neuron structure and leading in
turn to an accumulation of neuronal filaments (neurofibrillary
degeneration) and ultimately to nerve cell death (24)
AD has been considered a multifactorial disease associated with several
risk factors (figure 4). such as increasing age, genetic factors, head
injuries, vascular diseases, infections, and environmental factors (heavy
metals, trace metals, and others). The underlying cause of pathological
changes in Alzheimer’s disease (Aβ, NFTs, and synaptic loss) is still
unknown. Several hypotheses were proposed as a cause for AD but two of
them are believed to be the main cause: some believe that an impairment
in the cholinergic function is a critical risk factor for AD, while others
suggest that alteration in amyloid β-protein production and processing is
the main initiating factor. However, at present, there is no accepted
theory for explaining the AD pathogenesis (25)

Figure 4 the risk factor for alzheimer's Disease

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4.1. Alzheimer's Disease Hypothesis
4.1.1. Cholinergic Hypothesis

In the 1970s, neocortical and presynaptic cholinergic deficits were

reported to be related to the enzyme choline acetyltransferase (ChAT),
which is responsible for the synthesis of acetylcholine (ACh). Due to
the essential role of ACh in cognitive function, a cholinergic
hypothesis of AD was proposed. ACh is synthesized in the cytoplasm
of cholinergic neurons from choline and acetyl-coenzyme A by the
ChAT enzyme and transported to the synaptic vesicles by vesicular
acetylcholine transporter (VAChT) (figure 5) . In the brain, ACh is
involved in several physiological
processes such as memory, attention, sensory information, learning, and
other critical functions. Degeneration of the cholinergic neurons was
found to take place in AD and to cause alternation in cognitive
function and memory loss. Β-amyloid is believed to affect cholinergic
neurotransmission and to cause a reduction in the choline uptake and a
release of ACh. Studies demonstrated that cholinergic synaptic loss and
amyloid fibril formation are related to Aβ oligomers’ neurotoxicity and
to interactions between AChE and Aβ peptide. Additional factors also
contribute to the progression of AD, such as a reduction in nicotinic and
muscarinic (M2) Ach receptors, located on presynaptic cholinergic
terminals, and the deficit in excitatory amino acid (EAA)
neurotransmission, where glutamate concentration and D-aspartate
uptake are significantly reduced in many cortical areas in AD brains.
This is in addition to the use of cholinergic receptor antagonists such as
scopolamine, which was found to induce amnesia. This effect can be
reversed by using compounds that activate acetylcholine formation (26)

12
Figure 5 the pathway for the synthesis and transportation of
acetylcholine between presynaptic and postsynaptic nerve terminals

As a result, the cholinergic hypothesis is based on three concepts:

reduced presynaptic cholinergic markers in the cerebral cortex,
severe neurodegeneration of nucleus basalis of Meynert (NBM) in
the basal forebrain, which is the source of cortical cholinergic
innervation, and the role of cholinergic antagonists in memory
decline compared to the agonists, which have the opposite effect
(27)
4.1.2. Amyloid hypotheses
For decades, it was recognized that abnormal deposition of β-sheets
in the central nervous system has a strong correlation with
dementia, which led to the concept of the amyloid hypothesis.
However, it was found that the amyloid plaques (AP) also
deposit in normal healthy

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 brains with aging, which raised the question of whether AP deposition
is responsible for AD onset or not? Therefore, in the recent years,
alternative hypotheses were proposed for the non-inherited form of
AD (NIAD), but at present, the amyloid hypothesis remains the
most accepted pathological mechanism for inherited AD (IAD). The
amyloid hypothesis suggests that the degradation of Aβ, derived
from APP by β- and γ-secretase, is decreased by age or pathological
conditions, which leads to the accumulation of Aβ peptides (Aβ40
and Aβ42). Increasing the ratio of Aβ42/Aβ40 induces Aβ amyloid
fibril formation, resulting in neurotoxicity and tau pathology
induction, and consequently, leading to neuronal cell death and
neurodegeneration. AD risk factors and mutations of several genes
like APP, PSEN1, and PSEN2 were found to affect Aβ catabolism
and anabolism, which rapidly cause an accumulation of Aβ and fast
progression of neurodegeneration (28)
[Link]'s Disease Risk Factors
4.2.1. Aging
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(29). 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

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 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 (30).
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 (31).
[Link]
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 (32) . Herein , we discuss the strong genetic risk factor in

AD
1. Amyloid Precursor Protein (APP)

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 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 against AD by decreasing Aβ, Aβ40, and Aβ42
secretion (33) .
2. Presenilin-1 (PSEN-1) and Presenilin-2 (PSEN-2) PSEN1 and
PSEN2 genes are also the autosomal dominant form of EOAD
located on chromosomes 14 and 1, respectively. PSEN-2 and
PSEN-1 are homologous, with 67% similarity, with a difference
in the N-terminus and the hydrophilicregion. Mutation in PSEN1
gene is more common, with more than 200 mutations, while a
rare form with less than 40 mutations was identified in
the PSEN2 gene (34) .
PSEN1 is a core protein that activates the γ- secretase complex
and plays an important role in the production of Aβ from APP.
Knockout studies of PSEN1 showed synaptic dysfunction and
memory impairment in mice, which indicate its essential role in
maintaining memory and neurons(35) .
3. Apolipoprotein E (ApoE)
ApoE protein is a glycoprotein expressed highly in the liver and
brain astrocytes and some microglia

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 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 (36) 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 (37) .
ApoEε4 was also shown to be associated with vascular damage in
the brain, which leads to AD pathogenesis (38)
4. ATP Binding Cassette Transporter A1 (ABCA1) Adenosine
triphosphate (ATP)-binding cassette transporter A1 (ABCA1) is
part of a large ABC transporters family that regulate
cholesterol efflux in the circulation, like apolipoproteins-AI
(ApoAI), and into the brain, like ApoE. In addition, ABCA1
maintains the stability of ApoE lipidation and serves as a
mediator for high- density lipoprotein (HDL) generation, which
reflects its role in atherosclerosis and cardiovascular diseases.
Studies on the AD mice model showed that ABCA1 deficiency
increases

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 amyloid plaques and eliminates the lipidation of ApoE (39) .
In humans, a mutation in ABCA1 results in Tangier disease,
which is characterized by low levels of high-density lipoprotein
(HDL) and ApoAI in plasma, accumulation of cholesterol in
tissues, and AD pathogenesis (40) .
5. 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 [73].
Moreover, epigenetic factors like DNA methylation, histone,
and chromatin modifications were demonstrated to be involved
in AD (41) .
4.2.3. 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 : (42)
1. 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

18
 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
(43)
2. 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
(44) . The food processing causes degradation of heat-sensitive
micronutrients (e.g., vitamin C and folates), .

19
 Malnutrition is another risk factor for AD. Deficiency in
nutrients such as folate, vitamin B12, and vitamin D may cause a
decrease in cognitive function, in addition to the fact that
patients with AD suffer from problems associated with eating
and swallowing, which may increase the risk of malnutrition
(45)
3. 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.,
aluminum and lead)
(46) . Aluminum is used significantly in the industries such as
processed foods, cosmetics, medical preparations, medicines, and
others. In the body, aluminum is bound to plasma transferrin and
to citrate molecules that can mediate the transfer of aluminum to
the brain. Studies 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 (47) .
4.2.4. Medical factors
Several risk factors are related to the development of
Alzheimer’s disease. Adding to this list, older people with

20
 AD usually have medical conditions such as cardiovascular
disease (CVD), obesity, diabetes, and others. All of these
conditions are associated with increased risk of AD (48)
1. Cardiovascular Disease (CVDs)
CVDs are recognized as an important risk factor for AD, such as the
stroke that is associated with increased risk of dementia due to a
neural tissue loss, which enhances degenerative effect and influences
amyloid and tau pathology. Atrial fibrillation also causes embolisms
which leads to stroke and a decrease in memory and cognitive
functions. Moreover, heart failure affects the pumping function of
the heart and results in insufficient blood supply to the body and
hypo-perfusion of the brain that leads to hypoxia and neural damage.
The coronary heart disease’s hypothesis indicates that
atherosclerosis, peripheral artery disease, hypo-perfusion, and emboli
are all related to increased risk of AD. Hypertension is associated
with thickening of vessel walls and narrowing of the lumen which
reduce the cerebral blood flow, and in chronic cases, it may cause
cerebral edema, which all participate as risk factors for AD and
CVD. The CVD is a modifiable risk factor and by focusing on its
relationship with AD, a pathway to prevent and delay the disease can
be obtained (49)
2. Obesity and Diabetes
Obesity is a term used for too much body fat in individuals due to
consuming more calories than they

21
 burn and can be calculated by using the body mass index (BMI).
Increasing the body fat is associated with a decreased brain blood
supply which promotes brain ischemia, memory loss, and vascular
dementia. The obesity, unhealthy diet, and other factors can cause
impaired glucose tolerance (IGT) or diabetes, which is
characterized by hyperglycemia that affects peripheral tissues and
blood vessels. Chronic hyperglycemia can induce cognitive
impairment as a result of increasing amyloid-beta accumulation,
oxidative stress, mitochondrial dysfunction, and
neuroinflammation. Obesity is characterized by increasing pro-
inflammatory cytokines secretions from adipose tissue, which
stimulate macrophages and lymphocytes and eventually lead to
local and systemic inflammation. This inflammation promotes
insulin resistance, hyperinsulinemia, and as a consequence,
hyperglycemia. Obesity is a well-known risk factor for type 2
diabetes, CVDs, and cancer, which are identified as risk factors for
dementia and AD.
5. Newer strategies in early detection of Alzheimer’s disease
[Link]
A biomarker is an indicator considered for evaluation of any normal
biological as well as pathogenic processes and pharmacological
effects of any therapy. In the case of AD, a biomarker can be used to
assess the overall health and diseased condition of aged patients
(50) . An extracellular deposition of amyloid-β (Aβ) protein and
aggregated form of hyper phosphorylated tau protein in the brain
are two

22
 main pathological characteristics of AD (51) . Recently all the
important molecular biomarkers of Alzheimer’s disease were
critically discussed for their status and prospects by Lashley et al.
(2018) (52) . They detailed the use of cerebrospinal fluid and
blood biomarkers with positron emission tomography (PET)
imaging techniques for Aβ42 and phosphorylated tau
concentration, axonal and synaptic degeneration, glial activation,
trans active response DNA-binding protein 43 and α-synuclein
pathology determination. Fillit (2018) of the Alzheimer's Drug
Discovery Foundation recently emphasized the need for new
biomarkers for AD in Scientific American (53) . With increased
emphasis on drugs targeting beta-amyloid proteins all these
years, they have not yet yielded many positive results. Although
prognostic and diagnostic biomarkers are available for
Alzheimer’s disease, only a limited number of patients have
been tested with these clinically available biomarkers due to the
high cost and restricted access. Thus, studies are suggesting to
come up with an affordable and feasible blood test to be
performed in any clinical setup creating a big impact on AD
patients.
[Link] fluid (CSF) proteins
More specific to AD, CSF measures of Aβ1-42, t-tau, and p- tau
and molecular imaging using PET have become widely adopted
with improving assays and ligands. Some of the previous studies
carried out in vitro and human trials have indicated the role of
non-essential heavy metals cadmium (Cd), mercury (Hg), lead
(Pb), and arsenic (As) in causing Aβ protein aggregation along
with worrisome levels of tau

23
 hyper phosphorylation (54) . An ELISA assay called as
INNOTEST has been used for two decades for quantification of
t-tau, p-tau and Aβ42 in CSF which gives a unique
‘Alzheimer’s CSF profile’ where an increased level of t-tau and
p-tau is observed with decreased Aβ42 level (55) .C- reactive
protein (CRP) levels are majorly associated with ApoE
genotype and the CSF amyloid levels (56) . Mean CRP levels
decreased significantly in AD in study conducted by O'Bryant
et al. (2009 ) (57) . They also evaluated the link between CRP
and AD among Mexican Americans. In the mentioned study
they observed decreased levels of CRP among Mexican
American AD patients (58). The CRP has a role in amyloid
pathology as studied and shown in APP/PS1 (amyloid
precursor protein/presenilin 1) mice; pentameric CRP
dissociation takes place into monomeric forms prompted by
amyloid plaque (59). Monomeric CRP acts as a linker between
vascular trauma and inflammation and also is associated with
other events like plaque generation, neuronal injury, and
dementia (60) .
5.3. Genetic Markers
AD is complex and heterogeneous and is inherited according to
Mendelian genetics. There are more than 160 mutations reported
in three important genes which are responsible for coding
amyloid precursor, presenilin 1, and presenilin 2 (61). ε4 allele of
the APOE gene which occurs with a frequency of 14% is the
other major risk factor for developing AD; and its frequency
increases to ~40% in AD patients and is also related to the onset
of earlier age

24
 AD dementia and increased Aβ pathology. Amyloid
plaques are superabundant in ε4 carriers, with lower Aβ1-
42 concentration in CSF, with increased Pittsburgh compound B (PiB)
shown bound to Aβ aggregates on PET imaging [4]. Familial
Alzheimer's disease is inherited from parents and it currently accounts
for < 1% of the AD burden (62). Late-onset AD is genetically and
etiologically heterogeneous in nature, with innumerable genes and
environmental factors involved in disease progression rate and risk.
The strongest and most reliable genetic association involves the
epsilon 4 (ε4) allele at the ApoE locus for increased risk of late-onset
AD (63).
5.4. Brain imaging
There are profound changes that occur in the brain’s structure and its
function due to normal aging and AD. AD follows an extensive
cortical neuronal loss, with loss of connections in brain systems.
Recent advancements in brain imaging have supported unique
interruptions in functional neural networks. Concomitantly the
potential of brain imaging has expanded rapidly with innovations in
tools to acquire images and its analysis. Now they address structural,
functional, and molecular aspects with imaging in AD. Magnetic
resonance imaging (MRI) is being used for both structural and
functional and PET for evaluation of both amyloid and cerebral
metabolisms. Structural and functional MRI, fluoro-deoxy glucose
(FDG) and amyloid PET are the most commonly used imaging
techniques. Other MRI techniques in development that are also
adding to the knowledge of AD are diffusion tensor imaging

25
 (DTI) and associated tractography technologies, arterial spin
labeling measures of cerebral blood flow and PET tracers
targeted at the cholinergic system, microglial activation and
other tracers (64) . The PET imaging has utility of diagnostic
decision making, confidence in diagnosis and management
planning for patients with cognitive impairment (65) . Recent
developments in neuroimaging studies of AD provide useful
information to clinicians, including a new in vivo amyloid
imaging. MRI, single photon emission computed tomography
and 18F- fluorodeoxyglucose-positron emission tomography
(18F- FDG PET) are currently available for clinical use (66) .
6. Treatment
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 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 (67) . On the other hand,
overactivation of NMDAR leads to increasing levels of

26
 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 (68)
Unfortunately, only a few clinical trials on AD have been launched
in the last decade and their outcome was a big failure. Several
mechanisms have been proposed to understand AD pathology in
order to modify its pathway and develop successful treatments,
which include abnormal tau protein metabolism, β-amyloid,
inflammatory response, and cholinergic and free radical damage
(69) . On the other hand, most AD modifiable risk factors such as
cardiovascular or lifestyle habits can be prevented without medical
intervention. Studies showed that physical activity can improve the
brain health and reduce AD by activating the brain vascularization,
plasticity, neurogenesis, and reducing inflammation by decreasing
Aβ production, which all result in improving cognitive function in
older people. Moreover, the Mediterranean diet (MD), intellectual
activity, and higher education all may reduce the progression of
AD and memory loss and increase the brain capacity and cognitive
functions. Several studies revealed that multi-domain intervention
which includes lifestyle (diet, exercise, and cognitive training),
depression of AD symptoms, and controlling cardiovascular risk
factors, can increase or maintain cognitive function and prevent
new cases of AD in older people (70) .

7. Current strategies in the treatment of AD

27
 Till date, efforts are made to target and counterbalance the
neurotransmitter disturbances aimed to relieve symptoms of the
disease. A major drawback for the unavailability of a specific
treatment for the underlying pathology is that the emergence of
AD-related pathologic changes begins quite early, almost a decade
before the person shows the symptoms.
7.1. FDA APPROVED Medicines
Drugs that target cholinergic or glutamatergic neurotransmission
are currently available treatments for AD. These drugs only relieve
the symptoms. No drug is available that has a curative effect,
though there are many ongoing clinical trials for such drugs. These
newly developed molecules target the amyloid and tau
proteins(71). Currently approved drugs that affect cholinergic
transmission are three acetylcholinesterase inhibitors: donepezil,
rivastigmine, and galantamine. These drugs improve cognition in
the patient and ease the social and economic burden. These drugs
are effective in mild to moderate AD. To treat moderate to severe
form of AD, FDA approved Memantine in 2003. It is a NMDA
receptor antagonist and reduces the excitotoxicity observed in AD,
caused due to excess of glutamatergic transmission.
7.2. Gene Therapy in AD
Gene therapy interventions are aimed to tackle a disease at its
source, mostly a faulty DNA/gene/protein, to repair it and allow
the cells to fix the problem. After revealing various genes involved
in Alzheimer’s pathology, it opens up vast avenues for gene
therapy, which involves inserting new genetic material into

28
 living cells using viruses. Due to the recent developments in gene
therapy associated approaches in recombinant adeno-associated
viruses (rAAVs), the possibility for treating these diseases in
human beings is foreseen. In an effort to test the ability to
degenerate neurons in AD towards a nervous system growth factor
(NGF),(72) .

Figure 6 gives a combined overview of current and

future strategies of early detection and treatment of the
disease.

Current strategies in treatment and newer strategies in early

detection and treatment of Alzheimer’s disease. (A higher
resolution / colour version of this figure is available in the
electronic copy of the article).
7.3. Voice as a Biomarkers Using Artificial Intelligence

In addition to dementia Alzheimer's is also known to cause loss of

language skills which leads to difficulty in speaking and impair
communication with the environment. The clinical manifestations
manily include anomia and aphasia At different stages of AD,
patients experience different communication problems:
29
 1. Early stage (ES) - The patient is unable to detect the right
word in the speech or in the sentence frame.
2. Intermediate stage (IS) - They impoverish their vocabulary
and language of daily use.
3. Advanced stage (AS) - They speak very less and their response
is very limited.
Therefore, speech or voice analysis along with analysis of
emotional temperature of patients suffering from AD is very
important and can be used as a diagnostic tool for detecting
Alzheimer's in its preliminary stage (73) .
Based on all the approaches, it can be concluded that voice can be
used as a biomarker for Alzheimer. It is cheap, non-invasive
method which can identify AD even in its preliminary stages. More
detailed studies need to be done to identify the potential role of
voice along with other factors affecting it in a disease like
Alzheimer.
8. Ways to lower your risk of dementia
Did you know ?
Nearly 45% of all dementia cases may be prevented or delayed
(74).
Small changes can make a big difference to lower your risk
of dementia.
Healthy lifestyle habits

Healthy habits can benefit brain health by :

a) Reducing the chances of worsening memory loss.

b) Slowing the progression of dementia, including Alzheimer's.

30
Here are five lifestyle habits to keep your brain healthy:

1. Stay physically active .

Physical activity is important to keeping your heart, body and

brain healthy. What is good for your body is good for your
mind.

a) Regular physical activity can help you prevent, delay, or

manage chronic diseases, like dementia.
b) Experts recommend that adults get 150 minutes of physical
activity each week (at least 20 minutes/day).
2. Prevent or manage diabetes
When diabetes is not managed, important organs— like the
brain—can be damaged by too much sugar in the bloodstream.
The good news is type 2 diabetes can be prevented or delayed.
a) Learn how to manage your blood sugar if you have diabetes.
3. Manage your blood pressure.
High blood pressure can damage blood vessels and limit
blood flow to the brain, which does damage to the brain. It
also increases the risk of having a stroke, which can also
damage the brain (75).
a) Maintaining a healthy weight and taking your prescribed
blood pressure medications can help.
b) Talk with your Health Care Provider if you are concerned
about high blood pressure

4. Prevent or correct hearing loss.

Hearing loss is a very important risk factor for dementia.(76)
Researchers believe having hearing loss may make the brain
work harder at the expense of thinking and memory Hearing
loss also leads people to be less socially engaged, which is
31
important to remaining intellectually stimulated.(77)
A) Treating hearing loss (using hearing aids) may reduce the risk
of dementia.
B) If you have or are concerned about hearing loss, talk to a
hearing care professional to prevent, treat, or manage hearing
loss.
c) Try to limit or avoid drinking alcohol and smoking Over time,
excessive drinking can lead to high blood pressure or brain
injuries, both of which increase the risk of dementia. Current
smoking also increases the risk of developing dementia,
including Alzheimer's disease.
a) If you drink alcohol, do so in moderation. Learn about
alcohol use and your health.(78)
b) Quit smoking to reduce your risk dementia. Quitting smoking
also reduces other risks for dementia, like stroke, type 2
diabetes, and high blood pressure.(79)

32
9. Conclusion
This graduation project focuses on Alzheimer’s Disease (AD), a
progressive neurodegenerative disorder that mainly affects memory,
behavior, and thinking in the elderly. The disease progresses through
several stages, starting with mild cognitive impairment and ending with
severe dementia.

The project explains the biological mechanisms behind AD, including

the buildup of amyloid-beta (Aβ) plaques and neurofibrillary tangles
made from tau protein, which lead to cell damage and brain shrinkage. It
also covers other factors like oxidative stress, inflammation, and genetic
mutations (such as APP, PSEN1, PSEN2, and APOE).

In terms of diagnosis, the research presents both traditional methods like

brain imaging and CSF analysis, as well as new strategies like using
artificial intelligence to detect changes in voice and speech as early signs
of the disease.

Treatment options discussed include FDA-approved drugs that help with

symptoms, but not the root causes. The project also explores future
approaches like gene therapy and lifestyle changes (healthy diet, exercise,
mental activity) that may help delay disease progression.

In conclusion, Alzheimer’s Disease remains a complex condition with no

complete cure yet. However, early detection and a combination of medical
and lifestyle strategies can make a real difference in improving the quality
of life for patients.

33
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 ‫بيانات الطالب‪:‬‬

‫ﺳﻣﺎ إبراهيم عطيه حﺳين‬ ‫اسم الطالب‬

‫الميكروبيولوجى والكيمياء الحيوية‬ ‫البرنامج‬
‫تاريخ انعقاد البحث‬

‫‪Alzheimer's Disease‬‬ ‫عنوان البحث‬

‫د\ اﻣل نصر ﻣحﻣد‬ ‫المشرف‬

‫التقييم‪:‬‬

‫درجة الطالب‬ ‫الدرجة الكلية‬ ‫معيار التقييم‬

‫‪40‬‬ ‫اعداد البحث‬
‫‪60‬‬ ‫مناﻗشة البحث‬
‫‪100‬‬ ‫المجموع‬

‫لجنة اﻻمتحان‪:‬‬

‫التوﻗيع‬ ‫اللجنة اﻻمتحانية‬

‫عميد الكلية‬ ‫وكيل الكلية لشئون التعليم والطﻼب‬ ‫منسﻖ عام البرامج‬ ‫منسﻖ البرنامج‬
‫ا‪.‬د‪ /‬أحمد عبدالرحمن عسكورة‬ ‫ا‪.‬د‪ /‬احمد عبد الرحمن اسماعيل‬ ‫ا‪.‬د‪ /‬نجوى أبوالسعد‬ ‫ا‪.‬د‪ /‬جمال ربيع‬