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Maharshi Dayanand
University
Department of Pharmaceutical
Sciences
Assignment of:
Pathophysiology
On topic:
Pathophysiology of Alzheimer's
Disease
विद्यया विन्दतॆऽमृतम ्
Submitted By:
Deepanshu Goyal
B.Pharm 2nd Sem
Submitted To:
Dr. Vineet Mittal
Dept. of Pharmaceutical
Sciences
M.D.U. Rohtak
o Alzheimer's Disease or Alzheimer or just AD is An irreversible,
progressive cerebral disease of lowly know etiology that slowly
destroys intellectual and cognitive functions and hence the
ability to reason, remember, learn and imagine. This disease
lasts at least six months
o Alzheimer is the most common cause of Dementia, which is not a
disease itself, but a symptom. AD leads to a state of confusion,
loss or poor memory, decreased learning ability, mood and
emotional instability, personality changes and premature death.
o It affects many parts of Brain, but Neocortex, Amygdala and
hippocampus are most affected and severe dysfunction may
lead to Aphasia.
o The first case was studied and described by a German
Psychiatrist and Neuropathologist – Dr. Alois Alzheimer in 1906.
Introduction
Healthy
Neuron
Diseased
Neuron
Disintegrating
Microtubules
β Amyloid
Plaques
Tau Proteins
Microtubules
Axon
Epidemiology and
Statistics
 A bit more prevalent in Females with 65% of the
cases
 On average, a person with Alzheimer's lives four
to eight years after diagnosis, but can live as
long as 20 years.
 Generally it affects more to the people aged
more than 65 and around half of the cases being
in patients above the age 85.
 Currently around 4.5 Million people have AD and
predictions claim 1 in every 85 people will be
suffering from AD globally in 2050.
 Most of the cases are sporadic while 5-10% are
Familial.
Features Of
Alzheimer’s
Disease
Clinical o General Body weakness
o Bed ridden
o Memory Loss of recent events that
progresses to Dementia
o Loss of methodology of tasks and
motor skills of Familiar tasks
o Loss of Lingual ability i.e. ability to
converse.
o Mood and Personality Disturbances
o Disorientation to time and place
o More prone to infections, most
common being Rhinitis, Pneumonia
o Sleeplessness
o Anxiety
o Depression
Normal
Brain
Advanced
A.D. Brain
Macroscopic Examination of Brain shows:
1. Destruction of Neurons and
their connections
2. Neuritic-Amyloid Plaques
3. Neurofibrillary Tangles
4. Inflammation
5. Atherosclerosis of Brain
Arteries
6. Cortical Atrophy
7. Ridges of Brain called Gyri
Shrinks
8. Grooves of Brain called sulci
widens
9. Ventricular Enlargement
10. Shrinkage of Hippocampus
11. Pathologic changes In
Entorhinal Cortex
Stages of
Alzheimer’s
Disease
Mild
• Person may function
independently, drive, work
etc.
• Person feels of having
memory lapses
• Common Difficulties include
- Remembering word or
name
- Losing or Misplacing
objects
- Increased trouble in
Strategy, Planning etc.
• Can live well with proper
health maintenance
Moderate
• Longest Stage – Can last for
many years
• Require greater level of care
with the progression
• More Dementia symptoms
• Confusion with words, days
• Frustration and anger
• Change in sleep pattern
• Unexpected
Acts/delusions/suspicions
• Difficulty expressing
Thoughts
• Feeling moody or withdrawn
• Need assistance in
performing routine works
• Trouble controlling Bladder
Severe
• Severe Dementia symptoms
• Loss of ability to respond to
environment
• Inability to carry on a
conversation
• Expressing pain is difficult
• Round the clock assistance
required
• More vulnerable to infections
• Hospice care
The symptoms of Alzheimer's disease worsen over time with varying progression rate. Changes
in the brain related to Alzheimer's begin years before any signs of the disease. This time period,
which can last for years, is referred to as preclinical Alzheimer's disease.
It may be difficult to place a person with Alzheimer's in a specific stage as stages may overlap.
Pathophysiology of
Alzheimer’s Disease
Amyloid
β
Chopped at
here by β
secretase
Chopped at
here by α
secretase
Chopped at
here by ɣ
secretase
Cell membrane of Neuron
• In the Neuronal cell membrane, there is a protein
embedded called Amyloid Precursor Protein [APP] with
one end inside and other outside.
• Its function is related to growth and repair of Neuron,
but it gets used up/broken itself and recycled.
• It is chopped off by α, β and ɣ secretase enzymes with
the location of their splice can be seen in the image
beside.
• ɣ always works either with α that leads soluble products
or with β that leads insoluble product known as Amyloid
β, which is sticky, hence it makes clumps called β
Amyloid Plaques just outside the neuron.
• The clump when comes in synaptic cleft between two
neurons, disrupt the communication and signaling,
impairing the respective function, especially memory,
and can also initiate an immune response.
• These plaques may deposit in or around the brain’s blood vessels
causing Atherosclerosis or Amyloid Angiopathy respectively and later
on hemorrhage.
Cytoskeleton is a network of microtubules attached together with τ (tau)
proteins in the cell that acts like a pathway for internal transport, signaling
and structural support.. Without τ proteins, microtubules would detach
leading to disruption of Transport and signaling pathway.
• β Amyloid Plaques may activate kinase which attach phosphate group
to τ proteins which help in transport and bridge between two
microtubules and this activation cause tangling of these proteins
called Neurofibrillary tangles along with disruption of cytoskeletal
and microtubular function and further towards Apoptosis.
• Too much of Apoptosis leads to Atrophy of the various regions of the
brain, shrinkage of Gyri and widening of sulci and ventricles.
Pathophysiology of Alzheimer’s Disease
(continued…)
Sporadic
Late Onset
Genetic and Environmental Risk
factors
Genetic Relation based on number and
type of Apolipoprotein E alleles are
inherited. All help in breakdown of
Plaques but differ in effectiveness
No obvious Inheritance
pattern
Familial
Early Onset
Maybe caused by several gene mutations
Down Syndrome: Extra Chromosome 21
which is responsible in formation of APP
Autosomal Dominant gene
that speeds up the
progression
Difference in Sporadic and Familial
Alzheimer Disease
This image shows the
Neurofibrillary Tangle
Various Factors…
Neurochemical
Factors
1. Acetylcholine
2. Somatostatin
3. Substance P
4. Norepinephrine
Genetic
Factors
1. Apolipoprotein 4
(APOe4) allele –
Larger content of
β Amyloid Plaque
2. Down’s Syndrome
Environmental
and Lifestyle
1. Certain Infections
that can cross blood
Brain barrier
2. Use of statins
3. Heavy Metal and
other Toxins
4. Gender – Women are
more likely
Risk Factors
1. Family History
2. Chronic
Hypertension
3. Smoking
4. Alcoholism
5. Age
6. Diabetes
7. Cardiovascular
Diseases
ApoE3
ApoE2
ApoE ApoE4
Etiological Factors
Changes in Nerve cell Proteins
Accumulation of neurofibrillary
Tangles and Plaques
Granulo-vascular Degeneration
Loss of Cholinergic Nerve Cells
Loss of Memory, Function and
Cognition
Layout Diagram for Alzheimer’s
Disease
Hypotheses
Impaired Proteostasis
and Axonal Transport
Impaired Presenilin
(a component of
secretase) Function
Ca2+ DysregulationSoluble oligomer
production
Amyloid Plaque
Formation
Age, Oxidative
stress, Amyloid
β/Presenilin
dysfunction
Lysosome Autophagy
Dysfunction
Amyloid β
Mutation
Aggregated
Hyperphosphor
ylated τ
proteins
Due to amyloid
β
overproduction
Neurodegeneration
Synaptic Dysfunction
Neurotoxicity
Synaptic toxicity
Neurotoxicity
Diagnosis
Psychiatric and/or
Neuropsychological
assessments
Advanced
Imaging
Techniques
Patient’s and
Collateral
History
Clinical and
Pathological
Features
Advanced Brain imaging techniques:
Computed tomography (CT)
Magnetic Resonance Imaging
(MRI)
Positron Emission tomography
(PET)
Brain Biopsy
CSF
Examination
Electroencephal
ography (EEG)
Treatment
Pharmacological
• Acetylcholine esterase
inhibitors like Donepezil
prevent breakdown of
Acetylcholine, an important
chemical messenger
• NMDA receptor Antagonist
like Memantine to stop
overstimulation of NMDA
receptors by Glutamate
• Antidepressants
• Antipsychotics
• Anticonvulsants
Psychosocial
• Behavioral and Emotion
oriented approach
- Reminiscence therapy
- Validation Therapy
- Supportive Psychotherapy
- Sensory integration
- Stimulated presence therapy
• Cognition oriented approach
• Stimulation oriented approach
Caregiving
Since Alzheimer's has no cure
and it gradually renders people
incapable of tending for their
own needs…
Caregiving essentially is the
treatment and must be carefully
managed over the course of the
disease with provided Nursing
and Facilities to help the Patients
for his or her needs and keeping
them away from stress and
anxiety.
Sadly, but as of now there is no cure to Alzheimer’s Disease, but the following interventions can be underwent
to help the patient deal with the symptoms
Prognosis
With Alzheimer’s Disease, comes the increased
risk of Infections.
Along with this other problems related to age
such as Stroke, Cancer, Cardiovascular disease
etc. arise which may deteriorate the patient’s
physical and metal condition.
Prevention
Blockage of production of Amyloid in the brain as well as
breaking down of the β Amyloid once it is released from your
cell before its aggregation and development into insoluble
plaques. Research and Studies are under conduction to develop
an AD vaccine where immune responses may result in the
elimination of formation of Amyloid Plaques.
Bibliography:
The data was retrieved from various sources as follows:
• Kumar, Abbas et al – Pathologic Basis of Disease – Elsevier
Publishers – 9th edition – Pg. 1313 to 1317
• Grossman S, Carol MP – Porth’s Pathophysiology – Lippincott
Publishing – 9th Ed – Pg. 563 to 566
• www.nhs.co.uk – Alzheimer’s Disease Causes
• Kaushik M - Textbook of PATHOPHYSIOLOGY - PV publishers –
2017 – Pg. 268 to 270
• www.cdc.gov – What is Alzheimer’s Disease?
• www.wikipedia.org – Alzheimer’s Disease
• www.ajc.com – What you need top know about Alzheimer’s
Disease
• www.nia.nih.gov – Alzheimer’s Disease Fact Sheet
• www.medicalnewstoday.com – What to know about
Alzheimer’s Disease?
THANK
YOU…

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Pathophysiology of Alzheimer's disease

  • 1. Maharshi Dayanand University Department of Pharmaceutical Sciences Assignment of: Pathophysiology On topic: Pathophysiology of Alzheimer's Disease विद्यया विन्दतॆऽमृतम ् Submitted By: Deepanshu Goyal B.Pharm 2nd Sem Submitted To: Dr. Vineet Mittal Dept. of Pharmaceutical Sciences M.D.U. Rohtak
  • 2. o Alzheimer's Disease or Alzheimer or just AD is An irreversible, progressive cerebral disease of lowly know etiology that slowly destroys intellectual and cognitive functions and hence the ability to reason, remember, learn and imagine. This disease lasts at least six months o Alzheimer is the most common cause of Dementia, which is not a disease itself, but a symptom. AD leads to a state of confusion, loss or poor memory, decreased learning ability, mood and emotional instability, personality changes and premature death. o It affects many parts of Brain, but Neocortex, Amygdala and hippocampus are most affected and severe dysfunction may lead to Aphasia. o The first case was studied and described by a German Psychiatrist and Neuropathologist – Dr. Alois Alzheimer in 1906. Introduction Healthy Neuron Diseased Neuron Disintegrating Microtubules β Amyloid Plaques Tau Proteins Microtubules Axon
  • 3. Epidemiology and Statistics  A bit more prevalent in Females with 65% of the cases  On average, a person with Alzheimer's lives four to eight years after diagnosis, but can live as long as 20 years.  Generally it affects more to the people aged more than 65 and around half of the cases being in patients above the age 85.  Currently around 4.5 Million people have AD and predictions claim 1 in every 85 people will be suffering from AD globally in 2050.  Most of the cases are sporadic while 5-10% are Familial.
  • 4. Features Of Alzheimer’s Disease Clinical o General Body weakness o Bed ridden o Memory Loss of recent events that progresses to Dementia o Loss of methodology of tasks and motor skills of Familiar tasks o Loss of Lingual ability i.e. ability to converse. o Mood and Personality Disturbances o Disorientation to time and place o More prone to infections, most common being Rhinitis, Pneumonia o Sleeplessness o Anxiety o Depression
  • 5. Normal Brain Advanced A.D. Brain Macroscopic Examination of Brain shows: 1. Destruction of Neurons and their connections 2. Neuritic-Amyloid Plaques 3. Neurofibrillary Tangles 4. Inflammation 5. Atherosclerosis of Brain Arteries 6. Cortical Atrophy 7. Ridges of Brain called Gyri Shrinks 8. Grooves of Brain called sulci widens 9. Ventricular Enlargement 10. Shrinkage of Hippocampus 11. Pathologic changes In Entorhinal Cortex
  • 6. Stages of Alzheimer’s Disease Mild • Person may function independently, drive, work etc. • Person feels of having memory lapses • Common Difficulties include - Remembering word or name - Losing or Misplacing objects - Increased trouble in Strategy, Planning etc. • Can live well with proper health maintenance Moderate • Longest Stage – Can last for many years • Require greater level of care with the progression • More Dementia symptoms • Confusion with words, days • Frustration and anger • Change in sleep pattern • Unexpected Acts/delusions/suspicions • Difficulty expressing Thoughts • Feeling moody or withdrawn • Need assistance in performing routine works • Trouble controlling Bladder Severe • Severe Dementia symptoms • Loss of ability to respond to environment • Inability to carry on a conversation • Expressing pain is difficult • Round the clock assistance required • More vulnerable to infections • Hospice care The symptoms of Alzheimer's disease worsen over time with varying progression rate. Changes in the brain related to Alzheimer's begin years before any signs of the disease. This time period, which can last for years, is referred to as preclinical Alzheimer's disease. It may be difficult to place a person with Alzheimer's in a specific stage as stages may overlap.
  • 7. Pathophysiology of Alzheimer’s Disease Amyloid β Chopped at here by β secretase Chopped at here by α secretase Chopped at here by ɣ secretase Cell membrane of Neuron • In the Neuronal cell membrane, there is a protein embedded called Amyloid Precursor Protein [APP] with one end inside and other outside. • Its function is related to growth and repair of Neuron, but it gets used up/broken itself and recycled. • It is chopped off by α, β and ɣ secretase enzymes with the location of their splice can be seen in the image beside. • ɣ always works either with α that leads soluble products or with β that leads insoluble product known as Amyloid β, which is sticky, hence it makes clumps called β Amyloid Plaques just outside the neuron. • The clump when comes in synaptic cleft between two neurons, disrupt the communication and signaling, impairing the respective function, especially memory, and can also initiate an immune response.
  • 8. • These plaques may deposit in or around the brain’s blood vessels causing Atherosclerosis or Amyloid Angiopathy respectively and later on hemorrhage. Cytoskeleton is a network of microtubules attached together with τ (tau) proteins in the cell that acts like a pathway for internal transport, signaling and structural support.. Without τ proteins, microtubules would detach leading to disruption of Transport and signaling pathway. • β Amyloid Plaques may activate kinase which attach phosphate group to τ proteins which help in transport and bridge between two microtubules and this activation cause tangling of these proteins called Neurofibrillary tangles along with disruption of cytoskeletal and microtubular function and further towards Apoptosis. • Too much of Apoptosis leads to Atrophy of the various regions of the brain, shrinkage of Gyri and widening of sulci and ventricles. Pathophysiology of Alzheimer’s Disease (continued…)
  • 9. Sporadic Late Onset Genetic and Environmental Risk factors Genetic Relation based on number and type of Apolipoprotein E alleles are inherited. All help in breakdown of Plaques but differ in effectiveness No obvious Inheritance pattern Familial Early Onset Maybe caused by several gene mutations Down Syndrome: Extra Chromosome 21 which is responsible in formation of APP Autosomal Dominant gene that speeds up the progression Difference in Sporadic and Familial Alzheimer Disease This image shows the Neurofibrillary Tangle
  • 10. Various Factors… Neurochemical Factors 1. Acetylcholine 2. Somatostatin 3. Substance P 4. Norepinephrine Genetic Factors 1. Apolipoprotein 4 (APOe4) allele – Larger content of β Amyloid Plaque 2. Down’s Syndrome Environmental and Lifestyle 1. Certain Infections that can cross blood Brain barrier 2. Use of statins 3. Heavy Metal and other Toxins 4. Gender – Women are more likely Risk Factors 1. Family History 2. Chronic Hypertension 3. Smoking 4. Alcoholism 5. Age 6. Diabetes 7. Cardiovascular Diseases ApoE3 ApoE2 ApoE ApoE4
  • 11. Etiological Factors Changes in Nerve cell Proteins Accumulation of neurofibrillary Tangles and Plaques Granulo-vascular Degeneration Loss of Cholinergic Nerve Cells Loss of Memory, Function and Cognition Layout Diagram for Alzheimer’s Disease
  • 12. Hypotheses Impaired Proteostasis and Axonal Transport Impaired Presenilin (a component of secretase) Function Ca2+ DysregulationSoluble oligomer production Amyloid Plaque Formation Age, Oxidative stress, Amyloid β/Presenilin dysfunction Lysosome Autophagy Dysfunction Amyloid β Mutation Aggregated Hyperphosphor ylated τ proteins Due to amyloid β overproduction Neurodegeneration Synaptic Dysfunction Neurotoxicity Synaptic toxicity Neurotoxicity
  • 13. Diagnosis Psychiatric and/or Neuropsychological assessments Advanced Imaging Techniques Patient’s and Collateral History Clinical and Pathological Features Advanced Brain imaging techniques: Computed tomography (CT) Magnetic Resonance Imaging (MRI) Positron Emission tomography (PET) Brain Biopsy CSF Examination Electroencephal ography (EEG)
  • 14. Treatment Pharmacological • Acetylcholine esterase inhibitors like Donepezil prevent breakdown of Acetylcholine, an important chemical messenger • NMDA receptor Antagonist like Memantine to stop overstimulation of NMDA receptors by Glutamate • Antidepressants • Antipsychotics • Anticonvulsants Psychosocial • Behavioral and Emotion oriented approach - Reminiscence therapy - Validation Therapy - Supportive Psychotherapy - Sensory integration - Stimulated presence therapy • Cognition oriented approach • Stimulation oriented approach Caregiving Since Alzheimer's has no cure and it gradually renders people incapable of tending for their own needs… Caregiving essentially is the treatment and must be carefully managed over the course of the disease with provided Nursing and Facilities to help the Patients for his or her needs and keeping them away from stress and anxiety. Sadly, but as of now there is no cure to Alzheimer’s Disease, but the following interventions can be underwent to help the patient deal with the symptoms
  • 15. Prognosis With Alzheimer’s Disease, comes the increased risk of Infections. Along with this other problems related to age such as Stroke, Cancer, Cardiovascular disease etc. arise which may deteriorate the patient’s physical and metal condition. Prevention Blockage of production of Amyloid in the brain as well as breaking down of the β Amyloid once it is released from your cell before its aggregation and development into insoluble plaques. Research and Studies are under conduction to develop an AD vaccine where immune responses may result in the elimination of formation of Amyloid Plaques.
  • 16. Bibliography: The data was retrieved from various sources as follows: • Kumar, Abbas et al – Pathologic Basis of Disease – Elsevier Publishers – 9th edition – Pg. 1313 to 1317 • Grossman S, Carol MP – Porth’s Pathophysiology – Lippincott Publishing – 9th Ed – Pg. 563 to 566 • www.nhs.co.uk – Alzheimer’s Disease Causes • Kaushik M - Textbook of PATHOPHYSIOLOGY - PV publishers – 2017 – Pg. 268 to 270 • www.cdc.gov – What is Alzheimer’s Disease? • www.wikipedia.org – Alzheimer’s Disease • www.ajc.com – What you need top know about Alzheimer’s Disease • www.nia.nih.gov – Alzheimer’s Disease Fact Sheet • www.medicalnewstoday.com – What to know about Alzheimer’s Disease?