it is very useful. Specially for students in healthcare field. Brief discussion about alzeihmer's disease is given.

1. ALZEIHMER’s DISEASE
Prepared By:- Ashima Sharma
M. Pharm Sem-2
Dept. of Pharmacology
L. M College of Pharmacy

2. CONTENTS
INTRODUCTION
ETIOLOGY
PATHOPHYSIOLOGY AND RISK FACTORS
CLINICAL PRESENTATION
STAGES OF ALZEIHMER DISEASE
DIAGNOSIS
TREATMENT
REFRENCES

3. INTRODUCTION
Alzheimer's disease is a degenerative brain disorder of
unknown etiology which is the most common form of
dementia, that usually starts in late middle age or in old age,
results in progressive memory loss, impaired thinking,
disorientation, and changes in personality and mood. There
is degeneration of brain neurons especially in the cerebral
cortex and presence of neurofibrillary tangles and plaques
containing beta-amyloid cells

4. Origin of Alzheimer's Disease
The disease was first described by Dr.
Alois Alzheimer, a German physician,
in 1906. Alzheimer had a patient
named Auguste D, in her fifties who
suffered from what seemed to be a
mental illness. But when she died in
1906, an autopsy revealed dense
deposits, now called neuritic plaques,
outside and around the nerve cells in
her brain. Inside the cells were twisted
strands of fiber, or neurofibrillary
tangles. Since Dr. Alois Alzheimer's
was the first person who discovered
the disease, AD was named after him.
Auguste D
Alois Alzheimer

5. Comparison of a normal aged brain (left) and an
Alzheimer's patient's brain (right). Differential
characteristics are pointed out

6. INCIDENCE
This was common affecting 10% of the people at
the age of 65 and above and nearly 50% of those
aged 85.
About 3,60,000 new cases of Alzheimer’s are
diagnosed each year.
Scientists estimate that around 4.5 million people
now have AD

7. ETIOLOGY
 Loss of cholinergic neurons in the basal fore brain nuclei
 30-70% reduction of choline acetyl transferase activity in cortex and
hippocampus
 Activity of acetyl transferase is also decreased
 In the cortex nicotinic receptor density is decreased but muscarinic receptor
activity is not affected
 losses in the amount of nor-epinephrine and the dopamine β-hydroxylase and
decreases of serotonin causes non-cognitive symptoms of depression and
aggression
 Aβ is a fragment of amyloid precursor protein and accumulates as amyloid
plaques on neurons and may cause inflammation and cell death

8. PATHOLOGICAL CHANGES IN BRAIN

9. PATHOPHYSIOLOGY
Alzheimer's disease attacks nerves and brain cells
as well as neurotransmitters.
The destruction of these parts causes clumps of
protein to form around the brain's cells. These
clumps are known as 'plaques' and 'bundles'. The
presence of the 'plaques' and 'bundles' start to
destroy more connections between the brain cells,
which makes the condition worse.

10. DUE TO THE ETIOLOGICAL FACTORS
CHANGES OCCUR IN THE PROTIENS OF THE NERVE CELLS
OF THE CEREBRAL CORTEX
ACCUMULATION OF NEUROFIBRILLARY TANGLES AND PLAQUES
GRANULO VASCULAR DEGENERATION
LOSS OF CHOLINERGIC NERVE CELLS
LOSS OF MEMORY, FUNCTION AND COGNITION

11. AMYLOID PLAQUES
Genetic factors related to Amyloid β (Aβ)
 Chromosome 21, 14 and 1 became the focus of attention.
 Chromosome 14, the mutation causes an abnormal protein called presenilin 1
produced.
 Chromosome 1, the mutation causes yet another abnormal protein to be
This protein called presenilin 2, is very similar to presenilin 1.
 Protein called apolipoprotein E (ApoE) did bind quickly and tightly to beta
They also found that the gene that reduces ApoE was located in the same
chromosome 19.
 The gene that produces ApoE comes in several forms, or alleles- €2, €3 and
 ApoE €2 allele is relatively rare and may provide some protection against the
disease.

12.  ApoE €3 is the most common allele. Researchers think it plays a neutral role in
AD.
 ApoE €4 occurs is about 40% of all AD patients who develop the disease in later
life.
Transports of Aβ
 The majority of patients with so called sporadic or late onset AD do not have an
increased Aβ production or APP overexpression in the brain.
 The steady levels of Aβ are determined by the balance between its production
and clearance.
 Dysfunction in Aβ clearance is crucial for the accumulation of Aβ AD brains.
 So it is hypothesised that AD could be as result of the imbalance of the Aβ
production and its clearance.

13. ENZYME MEDIATED Aβ DEGRADATION
1. Neprilysin
 Rate limiting Aβ degrading enzyme in the brain.
 Inhibition of Neprilysin protein or disruption of the neprilysin gene results in a defect
in Aβ degradation.
 In AD brain, the level and activity of neprilysin decreases in the cortex and
hippocampus.
2. Insulin degrading enzyme (IDE)
 Another major enzyme for Aβ degradation in the brain.
 Levels of IDE in the brain decreases during aging.
 Defect in Aβ proteolysis by IDE also contributing to Aβ accumulation in the cortical
microvasculature of AD cases with cerebral amyloid angiopathy.

14. Enzymes act on the APP (amyloid precursor protein) and cut it into
fragments. The beta-amyloid fragment is crucial in the formation of senile
plaques in AD

15. Phosphorylated Tau
 Neurofibrillary tangles were purified and the microtubule associated protein tau
determined as the major protein component.
 Healthy neurons have an internal support structure partly made up of structures
called microtubules.
 They act like tracks, guiding nutrients and molecules from the body of the body
of the cell down to the ends of the axon and back.
 A special kind of protein, tau makes the microtubules stable. In AD, tau is
changed chemically.
 It begins to pair with other threads of tau and become tangled up together.
 When this happens, the microtubules disintegrate, collapsing the neurons
transport system.

16. In Alzheimer's disease, changes in tau protein lead to the
disintegration of microtubules in brain cells.

17. RISK FACTORS
a) Down's syndrome.
b) Family History.
c) Chronic high BP.
d) Head injuries.
e) Gender.
f) Smoking and Drinking

18. SIGNS
Ten warning signs of Alzheimer's disease
1) Memory loss
2) Difficulty to performing familiar tasks
3) Problems with language
4) Disorientation to time and place
5) Poor or decreased judgment
6) Problems with abstract thinking
7) Misplacing things
8) Changes in mood or behavior
9) Changes in personality
10) Loss of initiative

19. SYMPTOMS
 Confusion
 disturbances in short-term memory
 problems with attention and spatial orientation
 personality changes
 language difficulties
 unexplained mood swings

20. STAGES OF ALZHEIMER’S DISEASE
 PRECLINICAL AD

21.  MILD TO MODERATE AD

22.  SEVERE AD

23. DIAGNOSIS
 Mini-Mental State Examination (MMSE)
 Patient history
 Physical examination
 Laboratory tests
 Brain imaging
 Psychiatric assessments
 Mini-Cog Test

24. Mini-Mental State Examination
 One of the tests most commonly used to assess mental function.
 In the MMSE, a health professional asks a patient a series of
questions designed to test a range of everyday mental skills.
 The maximum scores is 30 points.
• 20-24 suggests mild dementia
• 1-20 suggests moderate dementia
• Less than 12 indicates severe dementia
 On average, the MMSE score of a person with AD decline about 2-4
points each year.

25. MRI AND PET SCAN
PET Scan of
normal brain
PET Scan of AD
brain

26. TREATEMENT
TWO CLASSES OF DRUGS ARE USED CURRENTLY:
1) Cholinesterase inhibitors
 Tacrine
 Donepezil
 Rivastigmine
 Galantamine
2) NMDA receptor antagonist
 Memantine

27.  Cholinesterase inhibitors
• Drugs that prevent the breakdown of acetylcholine, a
brain chemical involved in memory & other functions
related to thinking
 ↑ acetylcholine = ↑ cognitive abilities
• FDA-approved medications
 Donepezil (Aricept)
 Galantamine (Razadyne)
 Rivastigmine (Exelon)
 Tacrine (the first cholinesterase inhibitor approved in 1993, is rarely used now
due to its potential to cause liver damage)

28. By inhibiting acetylcholinesterase, these
drugs allow more acetylcholine to remain
activated
Increased levels of acetylcholine can help
maintain or improve cognitive abilities in
some people with dementia

29. 1) Donepezil
One of the most widely used drugs to treat the symptoms of
Alzheimer's disease. Donepezil is FDA-approved for mild, moderate,
and severe stages of the disease.

30.  Donepezil is available in tablet form or an orally disintegrating tablet form, and is commonly started at
5 mg a day.
 Can cross the blood-brain barrier.
 Dose: 5 mg daily x 4 weeks, may ↑ to 10 mg daily after 4-6 weeks
 Patients should be on 10 mg daily for ≥ 3 months before starting the 23 mg tablet
 Marginal improvement compared to 10 mg/day dose
 Relatively little peripheral anticholinesterase activity; generally well tolerated
Dose related side effects (N/V/D)
↑ dose = ↑ side effects
Tend to resolve with continued use
 Most common side effects are gastrointestinal
 Nausea / Vomiting / Diarrhea / Abdominal Cramping
 Side effects may become more tolerable over a few weeks. Can improve tolerability with:
 Slow titration
 Administration with food

31. 2) RIVASTIGMINE
 Rivastigmine is FDA approved for mild and moderate stages of the disease; it is also
approved for the treatment of mild to moderate dementia due to Parkinson's disease.
 Rivastigmine is available as a capsule, liquid, and patch.
 Rivastigmine is a cholinesterase inhibitor that prevents the breakdown of acetylcholine
and butyrylcholine in the brain by blocking the activity of two different enzymes.
Acetylcholine and butyrylcholine play a key role in memory and learning.
 When given orally, bioavailability is about 40% in the 3 mg dose. The compound can cross
the blood-brain barrier.

32. 3) Galantamine
 Galantamine is FDA-approved for mild and moderate stages of the disease
 Galantamine is a cholinesterase inhibitor that prevents the breakdown of acetylcholine in
the brain. Acetylcholine plays a key role in memory and learning; higher levels in the brain
help nerve cells communicate more efficiently. Galantamine also stimulates nicotinic
receptors to release more acetylcholine in the brain.
 Galantamine delays the worsening of Alzheimer's symptoms for 6 to 12 months in about
half of the people who take it.
 Galantamine is available in tablet and capsule form, and is commonly started at 4 mg
twice a day. If it's well tolerated after 4 weeks, the dosage may be increased to 8 mg twice
a day.

33.  Galantamine also comes in an extended release, once-a-day tablet.
NMDA receptor antagonist
 Memantine
 Memantine is an N-methyl D-aspartate (NMDA) antagonist that regulates the activity of
glutamate in the brain. Glutamate plays a key role in memory and learning, but excess
glutamate can lead to the disruption of nerve cell communication or nerve cell death.
 Studies involving Memantine have shown that the drug can slow the rate of decline in
thinking and the ability to perform daily activities in individuals who have moderate to
severe Alzheimer's disease
 A dysfunction of glutamatergic neurotransmission is thought to be involved in the etiology
of AD.

34. Side-effects of Memantine
 Appears to have fewer side effects than
acetylcholinesterase inhibitors
• Dizziness is the most common side effect
• Confusion and hallucinations have been reported in a
small amount of patients

36. Symptomatic treatments
 Antidepressants
 Antipsychotic
 Mood stabilizer
 Anxiolytic
 Hypnotics
ALTERNATIVE TREATMENTS
 Vitamin E
 Ginko biloba

37. Non pharmacological therapy
 Managing the environment of the patient with AD
 A safe, stable, comfortable environment will minimize the strain of
decreasing mental capacities and lessen confusion and agitation.
 Labeling items with names and laying out one change of clothes will
help maintain the patient's ability to perform the activities of daily
living.
 Providing regular exercise may reduce behaviors such as wandering
and restlessness.

38. REFRENCES
 H. P. Rang ,M.M Dale ,J.M.Ritter ,R,J.Flower ,Rang and Dale’s pharmacology , The
Alzheimer disease , Sixth Edition 2007 ,Churchill Livingstone ,508-520
 Eric T.Herfindal ,Richard A. Helthns ,Dick A.Golmey , David J Quan ,Textbook of
therapeutics, The Alzheimer disease ,8TH Edition 2007 ,722-742
 K.D.Tripathi , essentials of medical pharmacology , cns stimulant and cognition
enhancer,5th edition 2008 , jaypee brothers ,435-440
 Roger Walker ,Clive Edwards ,Clinical pharmacy and therapeutics
,neurodegenerative diseases ,Third Edition 2003 ,Churchill Livingstone ,725-743
 www.Alzheimer.org.in