pathogenesis , epidemiology and pharmacology of Alzheimer's disease.

1. ALZHEIMER’S
DISEASE
PREPARED BY: GROUP A
RIPHAHINTERNATIONAL
UNIVERSITY

2. CONTENTS
 What is Alzheimer’s disease
 Alzheimer’s vs dementia
 Pathology
 Pathophysiology
 Causes
 Signs and symptoms
 Diagnosis
 Genetics
 Neurochemistry
 Therapeutic approaches treatment of behavioral symptoms
treatment of cognitive symptoms
 Clinical overview
 Clinical summary
 Inhibition of neurodegeneration

3. WHAT IS ALZHEIMER’S
DISEASE
“IT IS PROGRESSIVE DISORDER THAT CAUSES THE BRAIN CELLS
TO WASTE (DENERATE) ANYWAY AND DIE”
 It is the most common cause of DEMENTIA.
 IT is an irreversible, progressive brain disorder that slowly destroys
memory and thinking skills and, eventually, the ability to carry out the
simplest tasks

4. ALZHEIMERR’S
FLOWCHART

5. ALZHEIMER’S VS DEMENTIA
• Dementia is an umbrella like term
that Alzheimer’s disease fall under.
• Alzheimer’s is the most
common type of dementia.
DEMMENTIA ALZHEIMER’S
It is a general term for decline in
mental ability. It is potentially
reversible.
It is loss of cognitive function of brain.
It is irreversible.
It is non specific because it is due to
many unknown causes.
It is specific because it is due to
known causes.

6. PATHOLOGY
“PHYSICAL CHANGES IN BRAIN LEAD TO THE PATHOLOGY OF
ALZHEIMER’S DISESE .”
The classic pathological signs of Alzheimer’s disease are:
• Amyloid plaques:
Aggregates of misfold proteins that form in spaces between nerve cells.
Accumulation of ß-amyloid protein
• Neurofibrillary tangles:
Insoluble twisted fibers found inside brain cells
Abnormal changes in tau protein
• Inflammation:
Excessive immune response that ends up killing the neurons instead of protecting
them.
Cytokines are boosted

7. NEUROFIBRILLARY TANGLES AND AMYLOID PLAQUES
BRAIN
INFLAMMATION
DIAGRAMMATIC
REPRESENTATION

8. CONT…

9. PATHOLOGICAL
FLOWCHART

10. PATHOPHYSIOLOGY
• Alzheimer’s disease is associated with brain shrinkage and localized loss of
neurons, mainly in the hippocampus and basal forebrain. The loss of
cholinergic neurons in the hippocampus and frontal cortex is a feature of the
disease.
Some pathological hypothesis clearly explains the pathophysiology of this disease :
 Hyperphosphorylated tau protein and amyloid β
hypothesis:
imbalance between β-amyloid (Aβ) production and clearance leads to various
types of toxic oligomers, namely protofibrils, fibrils and plaques depending upon
the extent of oligomerization.
 Oxidative stress hypothesis:
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced in
many normal and abnormal processes in humans.
.

11. CONT…
Neuron can interact with ROS, leading to the lipid peroxidation
reaction and molecular apoptosis, in addition, less glutathione in
neurons is also one of the causes of oxidative stress injury.
 Metal ion hypothesis:
Changes in the equilibrium of redox transition metals; mainly
copper (Cu), iron (Fe) and other trace metals. Their levels in the
brain are found to be high in AD.
 Cholinergic hypothesis:
Cholinergic receptor binding is reduced in specific brain regions
with mild to moderate AD and is related to neuropsychiatric
symptoms.

12. FLOWCHART

13. CAUSES
“Alzheimer's disease is thought to be caused by the abnormal
build-up of proteins in and around brain cells.”
• Amyloid plaques
• Neurofibrillary tangles
• Loss of neurons ( neurons of basal forebrain)
• Loss of cholinergic neurons.
• Alzheimer’s disease is a progressive condition, meaning that the
symptoms get worse over time. Memory loss is a key feature, and
this tends to be one of the first symptoms to develop.

14. SIGNS AND SYMPTOMS
• Memory loss that disrupts daily life
• Challenges in planning or solving problems
• Difficulty completing familiar tasks
• Confusion with time or place
• Trouble understanding visual images and spatial
relationships.
• New problems with words in speaking or writing.
• Misplacing things and losing the ability to retrace steps.
• Decreased or poor judgment.
• Withdrawal from work or social activities
• Changes in mood and personality

16. DIAGNOSIS
• Alzheimer disease is often a terrifying diagnosis for both
patients and their families.
• The only definitive way to diagnose Alzheimer’s disease is to
examine brain tissue under the microscope.
• The early stages of Alzheimer's disease are difficult to
diagnose ,a definitive diagnosis is usually made once
cognitive impairment compromises daily life activities.
• To diagnose Alzheimer's, doctors conduct tests to assess
memory impairment and other thinking skills, judge functional
abilities, and identify behavior changes.

17. DIAGNOSTIC TESTS
To assess for Alzheimer’s, there are quick
tests, such as
• Mini-Mental Status Exam (MMSE)
and mini-cog
• CT scan
• MRI
• PET (positron emission tomography)
• CSF examination
• EEG
• SPECT (Single-Photon Emission
Computed Tomography)
• Biomarkers
Technology involving positron
emission tomography (PET),
This imaging technique can spot
amyloid plaques in the brain.

18. GENETICS
• A family history of Alzheimer's disease increases a persons risk of
developing the disease themselves.
• Although environmental factors play a role but studies indicate
that 60-80% of disease is due to genetics.
• There are two types of Alzheimer’s—
1. early-onset
2. late-onset Both types have a genetic component
• Researchers have not found a specific gene that directly causes
late-onset Alzheimer's disease. However, having a genetic variant
of the Apo lipoprotein E (APOE) gene on chromosome 19 does
increase a person's risk

19. GENE MUTATION
The three single-gene mutations associated with early-onset
Alzheimer’s disease are:
i. Amyloid precursor protein (APP) on chromosome 21
ii. Presenilin 1 (PSEN1) on chromosome 14
iii. Presenilin 2 (PSEN2) on chromosome 1
Identification of these genes has led to a number of animal models
that have been useful to study the pathogenesis underlying AD.

20. GENE PROBABILITY
“Probability is used to measure the chances or
likelihood of an event to occur, a hypothesis
being correct, or a scientific prediction being
true”
A child whose biological mother or father carries a genetic
mutation for one of these three genes has a 50/50 chance
of inheriting that mutation. If the mutation is in fact
inherited, the child has a very strong probability of
developing early-onset Alzheimer’s disease.

21. NEUROCHEMISTRY
• The most striking neurochemical disturbance in AD is a
deficiency of ACh.
• The anatomical basis of the cholinergic deficit is atrophy and
degeneration of subcortical cholinergic neurons. can induce a
confusional state.
• AD, however, is complex and also involves multiple
neurotransmitter systems, including GLUTAMATE, 5HT, and
neuropeptides, and there is destruction of not only cholinergic
neurons but also the cortical and hippocampal targets that
receive cholinergic input.
• NOREPINEPHRINE and SOMATOSTATIN are also involved

23. THERAPEUTIC APPROACHES
• Treatment of AD has two approaches :
Treatment of cognitive symptoms
Treatment of behavioral symptoms.
TREATMENT OF
COGNITIVE SYMPTOMS
• Cognitive impairment is when a person has
trouble remembering, learning new things,
concentrating, or making decisions that affect
their everyday life. Cognitive
impairment ranges from mild to severe

24. DRUGS FOR COGNITIVE
SYMPTOMS
Two types of drugs are currently used to treat cognitive symptoms:
• Cholinesterase inhibitors
• Memantine (Namenda)
CHOLINESTRASE INHIBITORS
• Cholinesterase inhibitors. These drugs work by boosting levels of cell-to-cell
communication by preserving a chemical messenger that is depleted in the brain
by Alzheimer's disease. The improvement is modest.
• Cholinesterase inhibitors may also improve neuropsychiatric symptoms, such as
agitation or depression. Commonly prescribed cholinesterase inhibitors include
donepezil (Aricept), galantamine (Razadyne) and rivastigmine (Exelon).

25. CHOLINESTERASE INHIBITORS

26. MEMANTINE
• Memantine (Namenda). This drug works in another brain
cell communication network and slows the progression of
symptoms with moderate to severe Alzheimer's disease. It's
sometimes used in combination with a cholinesterase
inhibitor.

27. CHARACTERISTICS
Bioavailability ~100%
Metabolism Liver (<10%)
Elimination half-life 60–100 hours
Excretion Kidney

28. MECHANISM OF MENTAMINE

29. SIDE EFFECTS
COMMON
• CONFUSION
• DIZZINESS
• DOWSINESS
• HEADACHE
• INSOMNIA
• HALLUCINATION
• AGITATION
LESS COMMON
• VOMITING
• ANXIETY
• HYPERTONIA
• CYSTITIS
• INCREASED LABIDO

30. TREATMENT OF BEHAVIORAL
SYMPTOMS
• In addition to cognitive decline, behavioral and psychiatric symptoms in
dementia (BPSD) are common,
• These symptoms include irritability and agitation, paranoia and delusional
thinking, wandering, anxiety, and depression.
• A variety of pharmacological options are also available. Both cholinesterase
inhibitors and memantine reduce some BPSD.
• However ,they do not treat some of the most troublesome symptoms, such as
agitation.
• Benzodiazepines can be used for occasional control of acute agitation.
• Typical antipsychotic haloperidol may be useful for aggression

31. MEDICATION EXAMPLES
Antidepressants
( Low mood and irritability)
Anxiolytics
(anxiety, restlessness,
verbally disruptive behavior
and resistance)
Antipsychotic
medication
(hallucinations,
delusions, aggression,
agitation, hostility and
uncooperativeness)
Citalopram (Celexa) Lorazepam (Ativan) Aripiprazole (Abilify)
Fluoxetine (Prozac) Oxazepam (Serax) Clozapine (Clozaril)
Paroxetine (Paxil) Haloperidol (Haldol)
Sertraline (Zoloft) Olanzapine (Zyprexa)
Trazodone (Desyrel) Quetiapine (Seroquel)

32. CLINICAL OVERVIEW
AD has three major stages:
1- A “preclinical”
stage during which accumulation of Aβ and tau begins,
before any symptoms appear.
2- An “MCI stage”
with episodic memory loss ( repeated questions,
misplaced items, etc.) that is not severe enough to impair
daily function.
3- A “dementia stage”
with progressive loss of functional abilities.
Death usually ensues within 6–12 years of onset, most often
from a
complication of immobility such as pneumonia or pulmonary
embolism.

33. CLINICAL SUMMARY
• The typical patient with AD presenting in early stages of disease should probably be
treated with a cholinesterase inhibitor.
• Patients and families should be counseled that a realistic goal of therapy is to
induce a temporary reprieve from progression, or at least a reduction in the rate of
decline, rather than long-term recovery of cognition.
• As the disease progresses, memantine can be added to the regimen.
• Behavioral symptoms are often treated with a serotonergic antidepressant .
• Eliminating drugs likely to aggravate cognitive impairments, particularly
anticholinergics, benzodiazepines, and other sedative/hypnotics

34. INHIBITION OF
NEURODEGENERATION
• Inhibitors of β- and γ-secretase have been identified
and are undergoing clinical trials.
• Though they are effective in reducing Aβ formation,
several have proved toxic to the immune system and
gastrointestinal tract, and development has been
halted.
• A-ß plaques bind copper and zinc and metal ions
that promotes dissolution of plaques.

36. REFRENCES
BOOKS
 Rang&dale pharmacology
 Goodman Gillman pharmacology
 Lippincott pharmacology
 K.D triphati
SITES
 https://www.sciencedirect.com
 https://www.researchgate.net/figure/Fig-Pathophysiology-of-
alzheimers-disease_fig1_316619469
 Slideshare.com