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ALZHEIMER’S
DISEASE
Yash Tripathi
BMLS Sec B
230612032159

DEFINITION:
Alzheimer’s disease (AD) is a neurodegenerative disorder, characterized by
cognitive & behavioural impairment that significantly interferes with social &
occupational functioning.
Alzheimer’s disease is also known as senile dementia of the Alzheimer type (SDAT)
or simply Alzheimer’s, the most common form of dementia. It is an incurable, degenerative,
terminal disease.
AD results from an increase in the production or accumulation of specific protein
(β-amyloid protein) in the brain that leads to nerve cell death.

EPIDEMIOLOGY:
?According to 2015 report, AD affects 5.3 million people in US.
?AD was the 6th leading cause of death in 2015.
?AD and other dementias are more likely common in African Americans, than in whites.
?According to the WHO’s review in 2000, on the “global burden of dementia”:
approximate rates of dementia are under 1% in persons aged 60-69 years and 39%
in persons aged 90-95 years, prevalence doubles with every 5 years of age (within
the above ranges).

ETIOLOGY:
The exact etiology of Alzheimer’s disease is not known and associated with risk factors.
But stated that there are several genetical and environmental factors have been explored as
potential causes of the Alzheimer’s disease.
Other factors include:
1. Advancing age
2. Family history
3. Trauma
4. Education
5. Vascular disease like stroke etc.

RISK FACTORS:
The common risk factors
for developing Alzheimer’s
disease are:
?Increased age (over 65 years of age)
?Hypertension (high blood pressure)
?Increased cholesterol levels
?Coronary artery disease
?Diabetes
Other risk factors are:
?Genetics
?Smoking and alcohol use
?Plasma homocysteine
?Down syndrome
?Mild cognitive impairment

PATHOPHYSIOLOGY:
The brain has billions of neurons, each with an axon and many dendrites. To stay
healthy, neurons must communicate with each other, carry out metabolism and repair
themselves. AD disrupts all three of these essential jobs.
There are two signature lesions in Alzheimer’s disease. They are:
1. Neuritic plaques/ β-amyloid plaques, which are dense deposits of protein and cellular
material that accumulate outside and around nerve cells.
2. Neurofibrillary tangles (NFT’s), which are twisted fibers that build up inside the nerve
cell.

1. NEURITIC PLAQUES:
Deposits of a protein fragment called β-amyloid, that accumulates in the spaces between
the nerve cells (neurons).
APP (amyloid precursor protein) is the precursor of amyloid plaque.
a) APP sticks through the neuron membrane.
b) Enzymes like β-secretase and α-secretase cut the APP into fragments of protein
(neurotoxic Aβ42 fragment), including β-amyloid.
c) β-amyloid fragments come together in clumps to form plaques.
In AD, many of these clumps form, disrupting the work of neurons. This affects the
hippocampus and other areas of the cerebral cortex.

APP (amyloid precursor protein)
Cleaved by β-secretase and α-secretase
Mutation of amyloid precursor protein on chromosome no. 21
Increased production of amyloid precursor protein
Produces of amyloid protein
Accumulation of β-amyloid protein
(due to increased production of APP)
Directly neurotoxin
Alzheimer’s disease

2. NEUROFIBRILLARY TANGLES
(NFT’S):
Neurons have an internal support structure
partly made up of microtubules. A protein called
“tau” helps to stabilize microtubules. In AD, “tau”
changes, causing microtubules to collapse and
“tau” proteins clump together to form
neurofibrillary tangles.

CONTD
… Although autopsy studies show that most people develop
some plaques & tangles as they age
Those with AD tend to develop them far more & in a predictable pattern
They develop in the areas important for memory
before spreading to other regions
Plaques & tangles disable/block communication among neurons
Gradually spread to other areas of brain
Causes symptoms of Alzheimer’s disease

SYMPTOMS:
The symptoms of AD are classified as:
1. Cognitive symptoms
2. Non cognitive symptoms
3. Functional symptoms

CONTD…
1. Cognitive symptoms:
? Memory loss (poor recall
and losing items)
? Aphasia (circumlocution and anomia)
? Apraxia, agnosia,
? Disorientation (impaired perception of
time and unable to recognize familiar
people)
? Impaired executive function.
2. Non cognitive symptoms:
? Depression, psychotic
(hallucination and delusions).
symptoms
? Behavioural disturbances (physical and
verbal aggression, motor hyperactivity,
uncooperativeness, wandering, repetitive
mannerisms and activities and
combativeness).
3. Functional symptoms:
? Inability to care for self (dressing, bathing,
eating etc.)

PHARMACOLOGICAL TREATMENT:
1. Cholinesterase inhibitors:
MOA:
These drugs selectively inhibit acetyl cholinesterase, the enzyme responsible for the
destruction of acetyl choline. Thus, acetyl choline gets accumulated (improves Ach
availability) and produces cholinergic effects.
Acetyl CoA + Choline
Choline acetyl transferase
Acetyl choline (Ach)
Acetyl cholinesterase
Choline + Acetate
Cholinesterase inhibitors
(e.g. donepezil, rivastigmine, galantamine)

CONTD…
2. NMDA receptor antagonists (Memantine):
MOA:
The N-methyl-D-aspartate receptor (also known as NMDA receptor) is a glutamate
receptor and ion channel protein found in nerve cells. The NMDA receptor is very
important in controlling synaptic plasticity and memory function. NMDA type
glutamate receptors may be over activated in AD (glutamatergic excitotoxicity).
Memantine binds preferentially to NMDA receptor and blocks it. Blocking usually occurs
only under conditions of excessive stimulation and not under neurotransmission.

CONTD
… Memantine
Blocks
NMDA receptor (blocks glutamate)
Prevents too much calcium from moving into the brain cells
Reduces excessive stimulation
Reduces the symptoms of Alzheimer’s disease
? ADRs: Hypertension, cataract, CVA, thromboembolism etc.
? Uses: It is commonly used for moderate-severe dementia in patients with AD.
? Dose: Memantine: 5mg OD (initial dose); 20mg/day (Max. dose)

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