Alzheimer's disease is a progressive brain disorder that destroys memory and thinking skills. It results from abnormal buildup of proteins in the brain that cause nerve cell death. Risk increases with age and family history. Symptoms start with mild memory loss and worsen over time, eventually causing severe brain damage. The only way to definitively diagnose is through brain autopsy. Currently, there is no cure and treatment focuses on managing symptoms and slowing progression.

2. Under supervision of:
Prof. Dr. Seham Abo Shosha
Presented by:
Sara Ahmed Youssry

3. Alzheimer's disease (AD)
Is a slowly progressive disease of the brain that is characterized by
impairment of memory and eventually by disturbances in planning,
language, and perception.
Results from an increase in the production or accumulation of a
specific protein (beta-amyloid protein) in the brain that leads to nerve
cell death.
Epidemiology
The likelihood of having Alzheimer's disease increases after the age of
70 and may affect around 50% of persons over the age of 85.
However, Alzheimer's disease is not a normal part of aging.

4. Risk factors :
•Increased age. The biggest risk factor for Alzheimer's disease
•Genetic risk factors
-The best-studied "risk" gene is the one that encodes
apolipoprotein E (apoE).
The apoE4 form of the gene has been associated with increased
risk of Alzheimer's disease.
Persons with one copy of the E4 gene usually have 2-3fold
increased risk.
Persons with two copies of the E4 gene have about 9-fold
increase in risk.
-Mutations in one of three genes: those encoding amyloid
precursor protein (APP) and presenilins 1 and 2

5. •Traumatic head injuries earlier in life, particularly among those
with the apoE 4 gene.
•limited formal education usually less than eight years .
It is not known whether this reflects a decreased "cognitive reserve"
or other factors associated with a lower educational level.
•women have a higher risk for Alzheimer's disease than men.
-women live longer than men
-The role of estrogen in Alzheimer's disease remains an area
of research focus.

7. Symptoms of Alzheimer's disease
The course of Alzheimer's disease is not the same in every person,
but symptoms seem to develop over 3 stages.
Very early signs and symptoms
Memory problems are typically one of the first signs of AD.
A) Mild Alzheimer's disease
As the disease progresses, memory loss worsens, and changes in other cognitive
abilities are evident. Problems can include:
Getting lost
Trouble handling money and paying bills
Repeating questions
Poor judgment
Mood and personality changes
Alzheimer's disease is often diagnosed at this stage

8. B) Moderate Alzheimer's disease
In this stage, damage occurs in areas of the brain that control language, reasoning,
sensory processing, and conscious thought. Symptoms may include:
Increased memory loss and confusion
problems recognizing family and friends
inability to learn new things
Hallucinations.
impulsive behavior
C) Severe Alzheimer's disease
People with severe Alzheimer's are completely dependent on others for their
care. Near the end, the person may be in bed most or all of the time. Their
symptoms often include:
Inability to communicate
Weight loss
Skin infections
Difficulty swallowing
Increased sleeping
lack of control of bowel and bladder

9. What causes Alzheimer's disease?
It is a neurodegenerative disease, caused by progressive brain cell
death that happens over a course of time.
The total brain size shrinks with Alzheimer's - the tissue has
progressively fewer nerve cells and connections.

10. Postmortem/autopsy will always show tiny inclusions in the nerve
tissue, called plaques and tangles:
•Plaques are found between the dying cells in the brain - from the
build-up of a protein called beta-amyloid (amyloid plaques).
•The tangles are within the brain neurons - from a disintegration of
another protein, called tau.

11. Several competing hypotheses exist trying to
explain the cause of the disease:
-Genetics:( Amyloid hypothesis ) : The most important one
Mutations in one of three genes: those encoding amyloid precursor
protein (APP) and presenilins 1 and 2 increase the production of a
small protein called AB42, which is the main component of senile
plaques ( Familial type of AD )
APOE4, is a major genetic risk factor for AD leading to excess
amyloid buildup in the brain ( Sporadic type of AD )

12. Tau hypothesis
Tau protein abnormalities initiate the disease
cascade. Hyperphosphorylated tau begins to pair with other threads
of tau. Eventually, they form neurofibrillary tangles inside nerve cell
bodies. When this occurs, the microtubules disintegrate, collapsing the
neuron's transport system. This may result first in malfunctions in
communication between neurons and later in the death of the cells
Other hypotheses
-Age-related myelin breakdown in the brain. Iron released
during myelin breakdown cause further damage. Homeostatic
myelin repair processes contribute to the development of
proteinaceous deposits such as beta-amyloid and tau.
-Oxidative stress may be significant in the formation of the
pathology

13. Mechanisms linking AD pathogenesis to apoptosis.
The amyloid hypothesis points to the accumulation of betaamyloid peptides ( the toxic form of the protein ) as the central event
triggering neuron degeneration “cascade” that results in neuron
death (apoptosis) and cognitive impairments
Aß has been shown to destabilize neuronal calcium homeostasis,
generally leading to an increase in cytosolic calcium which can then
trigger neuronal apoptosis
Aß resulted in increased p53 levels, which were sufficient to
increase Bax protein and nuclear fragmentation
In vitro Aß induces expression of pro-apoptotic Bcl-2 proteins,
including Bax, and down regulation of anti-apoptotic
members such as Bcl-2, Bcl-xL and Bcl-w.

14. Aβ associated mitochondrial dysfunction leading to cognitive
decline in AD:
•Decreased mitochondrial motility resulting in disorganized synaptic
mitochondrial distribution
•Decreased mitochondrial ATP provision and respiratory function
•Decreased cytochrome oxidase activity
•Elevated mitochondria-associated oxidative stress
•Increased mitochondrial permeability
•Decreased mitochondrial Ca2+ modulating capacity and
Ca2+ accumulation
•Release of pro-apoptogenic factors from mitochondria
•Membrane potential collapse
•Increased free radical production
Increased mitochondrial fragmentation (important event early
in apoptosis

15. Aβ can have toxic effects via direct and indirect mechanisms
including inducing local inflammation.
Eg. interleukins (IL), TNFα, and TNFβ
Increased amounts of cell injury or death of neurons can occur when
the inflammatory response is chronic and uncontrolled in nature
Impact of tau on toxicity,
that tau becomes more hyperphosphorylated with disease
progression and leads to greater dendritic toxicity.

16. In particular, FasL appears to play an important role in Aβmediated neurotoxicity. Exposure of cortical neurons to Aß activates
c-Jun N-terminal kinase (JNK). JNK is required for the activation of
the c-Jun transcription factor, which in turn stimulates the
transcription of several key target genes, including the death inducer
FasL. The binding of FasL to its receptor Fas then induces a cascade
of events, leading to caspase activation and, ultimately, apoptosis .
In parallel, tumor necrosis factor alpha (TNF ), tumor necrosis
factor receptor 1 (TNF-R1)
and TNF-R1-associated death domain protein (TRADD) have all
been found to be increased in AD.

18.  Alterations in the distribution of different neurotrophic factors and
in the expression of their receptors such as the brain derived
neurotrophic factor (BDNF) have been described in AD
Initiate apoptosis

21. How is AD Diagnosed?
•Asking questions about the person’s general health, any past
medical problems, and the ability to do daily activities
•Memory tests, problem solving strategies, attention, counting
•Tests of blood, urine, or spinal fluid
•Brain scans
Computed tomography (CT) or magnetic resonance imaging (MRI) of the brain.
In the early stages of dementia, brain image scans may be normal.
In later stages, an MRI may show a decrease in the size of different areas of the
brain.
While the scans do not confirm the diagnosis of AD, they do exclude other causes
of dementia (such as stroke and tumor).
However, the only way to know for certain that someone has AD is to examine a
sample of their brain tissue after death.

22. Treatment
There is no cure for AD. The goals of treatment are:
-Slow the progression of the disease.
-Manage symptoms, such as behavior problems, confusion, and sleep
problems
-Change home environment so you can better perform daily activities
-Support family members and other caregivers
a) DRUG TREATMENT
Medicines are used to help slow down the rate at which symptoms
become worse. The benefit from these drugs is usually small.
Modulate neurotransmitters, either acetylcholine or glutamate.
(reduction in the activity of cholinergic neurons is a feature of AD).
Eg.cholinesterase inhibitors (ChEIs) and a partial N-methyl-D-aspartate
(NMDA) antagonist.

23. Psychotropic medications have been used to treat behavioral
symptoms:
-Antidepressants
-Anxiolytics
-Antiparkinsonian agents
-Beta-blockers
-Antiepileptic drugs (for their effects on behavior)
-Neuroleptics
b) Potential surgical treatments in the future may include the use
of devices to infuse neurotrophic factors, such as growth factors,
to palliate AD.
c) If the patient becomes a danger to him/herself or others, shortterm hospitalization may be indicated