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Md. Amran Howlader
Clinical pharmacy and pharmacology
Alzheimer’s is the most common cause of
dementia in adult life and is associated with the
selective damage of brain regions and neural
circuits critical for memory and cognition
The pathogenesis of this disease is complex, and
involves many molecular, cellular, and
physiological pathologies
The neurons in the neocortex, hippocampus,
amygdala, and the basal forebrain cholinergic
system are the most affected brain regions
What is Alzheimer’s Disease?
Alzheimer's disease (AD) is an irreversible, progressive disorder
in which brain cells (neurons) deteriorate, resulting in the loss
of cognitive functions, e.g.
judgment and reasoning,
movement coordination
which makes it hard for the person to work or take part in dayto-day life. The death of the nerve cells occurs gradually over a
period of years.
This computer graphic compares the brain of a patient with
Alzheimer’s disease, left, with a normal, healthy brain, right. A
degenerative disease, Alzheimer’s disease causes brain tissue to
shrink and leads to a gradual, irreversible loss of memory and
Symptoms of Alzheimer's Disease
The earliest recognized symptoms of Alzheimer's disease
•often mild memory loss
•a sufferer may begin to forget recent
conversations or what year it is
•There may be disorientation (e.g.
getting lost in familiar surroundings),
•problems with routine tasks (like using
a microwave), and
•changes in personality and judgment.
As the disease progresses, patients begin to have
•difficulty with the activities of daily living
•sleep disturbance,
•difficulty recognizing family and friends.
In the most advanced stages of the disease
•loss of the ability to speak,
•weight loss,
•lack of appetite and
•loss of bowel and bladder control
Patients require round-the-clock caregiving.
There are now more than 5 million people in the United
States living with Alzheimer’s.
Every 72 seconds, someone develops Alzheimer’s
Alzheimer’s disease predominantly affects the elderly65-74years-19%
Women are more prone to develop AD
Risk factors
•Age-↑with every decade of adult life
•Family history-accounts for <10
•Untreated chronic hypertension-for mental
•Ethnic groups- African-Americans at greater
•Lower education & Economic group
•Gender- women are↑risk
•Excessive metal ions e.g. zinc, copper
Most common cause of dementia
 atrophy
of cortex; loss of cortical and
subcortical neurons, especially cholinergic
 senile plaques and neurofibrillary tangles
 role of -amyloid
 inflammatory response
 oxidative injury & free radical formation
Characteristics of AD- progressive memory loss
Diagnosis of AD-lesion
The biochemical defects responsible for
there changes have not been identified,
but there are much evidence of a marked
decrese in choline acetyltransferase and
other markers of cholinergic neuron
activities and for changes in brain
glutamate, dopamine, norepinephrine,
cholinergic, serotonin and somatostatin.
Eventually cholinergic and perhaps other
neurons die or are destroyed.
Amyloid Plaque Formation
Alzheimer’s patients show numerous
plaques which are composed of 4 kD
Amyloid-beta (A-beta) peptides, which are
derived from beta amyloid precursor
proteins (APPs)
glycoprotein of 110-135 kDa that is
proposed to normally behave in the brain
as a cell surface signaling molecule
Presenilin 1 (PS1) and presenilin 2 (PS2) are
highly homologous 43-50 kD proteins with eight
transmembrane domains
Presenilin’s make crucial contributions to
neurodegeneration in AD
Presenilin’s are crucial components of the
enzymes that work to cleave APP, and mutations
in presenilins cause the production of A-beta42
and A-beta43 peptides (insoluble forms of Abeta)
The production of A-beta
production by processing of APP
Amyloid Plaque formation
About 90% of the secreted A-beta peptides
formed from processing of APP are A-beta40, a
soluble form of the peptide
About 10% of secreted A-beta peptides are Abeta42 and A-beta43
A-beta42 and A-beta43 are highly fibrillogenic,
readily aggregated, and neurotoxic
Amyloid Plaque formation
Alignment of several strands of A-beta
show that A-beta42 and A-beta43
preferentially form networks of salt
linkages and strong hydrogen bonds
between ionized side chains of opposite
charge which thus form the observed
Schematic representation of a
parallel beta sheet in an amyloid
Micrographs of amyloid fibrils
Micrograph of amyloid fibres
Neurofibrillary pathology
Intracellularly, alzheimer’s patients show
neurofibrillary pathology
Affected neurons accumulate tau and
ubiquitin immunoreactivities within
neurofibrillary tangles, in cell bodies and
dendrites, and in dystrophic neuritis
In the brain, plasminogen and its proteolytic
fragment are abundant in the hippocampus
It has been hypothesized that brains of patients
with AD may have lower levels of plasmin
The higher production of amyloid peptide
together with less efficient degradation would to
A-beta accumulation and aggregation
Early Onset Alzheimer’s
Most cases of early onset AD are familial
autosomal dominant disorders caused by
mutations in APP, PS1, and PS2
Various substitutions have been studied
and they have found various mutations
that cause the individuals to secrete a
higher fraction of A-beta42 and/or Abeta43 peptides
Late Onset Alzheimer’s
In late onset alzheimer’s, there are no
specific gene mutations that are
associated with the inheritance of the
However, specific alleles of apoliprotein E4
(apoE) and alpha2 macroglobulin are
associated with increased risk of
Amyloid Hypothesis
The trigger for alzheimer’s disease is the A-beta
peptide, and the accumulation of this peptide in
the form of plaques is the initiating molecular
The plaques trigger an inflammatory response,
neuronal cell death, and gradual cognitive
The rest of the disease process, including
formation of neurofibrillary tangles containing
tau protein, is caused by an imbalance between
A-beta production and A-beta clearance
The sequence of
leading to AD
by the amyloid
Postulated evolution of structural
abnormalities and evidence of Abeta deposits in the hippocampus
Support for the Amyloid Hypothesis
The A-beta peptide is the primary component of
the necrotic brain tissue
Mutations in the gene encoding the tau proteins
cause frontotemporal dementia with
However, parkinsonism is characterized by
severe deposition of tau in neurofibril tangles in
the brain, but there is no deposition of amyloid
Support for the Amyloid Hypothesis
Growing evidence indicates that genetic
variability in A-beta catabolism and
clearance may contribute to the risk of
late onset of AD
Problems with the amyloid
The number of amyloid deposits in the brain do not
correlate well with the degree of cognitive impairment
that the patient experienced in life. In some cases,
individuals without symptoms of AD have many cortical
A-beta deposits.
The amyloid hypothesis remains controversial because a
specific neurotoxic species of A-beta and its effects on
neuronal function have not been defined in vivo
Problems with the amyloid
Another concern is that the fact that all AD causing
mutations in APP, PS1, or PS2 increase A-beta
deposition, yet the degree to which a particular mutation
affects A-beta production in cell culture shows no simple
correlation with the age at which it first produces
The degree of dementia appears to correlate with
soluble A-beta species. Several lines of evidence have
converged recently to demonstrate that soluble
oligomers of A-beta, instead of monomers or insoluble
amyloid fibrils, may be responsible for synaptic
dysfunction in the brains of AD patients and in animal
Calcium Hypothesis
Calcium modulates many neural processes, including
synaptic plasticity and apoptosis
Dysregulation of intracellular calcium signaling has been
implicated in the pathogenesis of alzheimer’s disease
Increased intracellular calcium elicits the characteristic
lesions of this disorder, including the accumulation of
amyloid-beta, the hyperphosphorylation of TAU and
neuronal death
Every gene that is known to increase susceptibility to
Alzheimer’s disease also modulates some aspect of
calcium signaling
Calcium Hypothesis
The disruption of calcium homeostasis
might be one of the principal mechanisms
by which A-beta manifests its
A-beta has been shown to destabilize
neuronal calcium homeostasis, generally
leading to an increase in cytosolic calcium
which can then trigger neuronal apoptosis
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Treatment Strategies
1. One could attempt to partially inhibit proteases that
generate A-beta from APP
2. One could attempt to prevent the oligomerization of
A-beta or enhance clearance from the cerebral cortex
3. An anti-inflammatory strategy based on the
observation that a cellular inflammatory response in the
cerebral cortex is elicited by the progressive
accumulation of A-beta
Treatment Strategies
4. Based on modulating cholesterol
homeostasis. Chronic use of cholesterol
lowering drugs have been associated with a
lower incidence of Alzheimer’s disease
Current Treatment for AD
Acetylcholinesterase inhibitors:
current agent of choice is donepezil
(Aricept) 1x daily;
MOA: inhibit acetylcholinesterase and increase
cholinergic transmission
indicated for mild to moderate AD
2nd generation: rivastigmine (Exelon) 2x daily,
 problems: symptomatic treatment with significant
adverse effects: muscle cramps, n/v, diarrhea,
Memantine (Namenda) approved 2004
MOA: block NMDA receptor and blocks excess
 indicated for moderate to severe AD
 Can be used in combination with Ache
Prevention approaches
MOA: prevent or slow accumulation of
beta amyloid,
 antioxidants,
antiinflammatory NSAID’s,
statins, Vitamin E, selegiline, curcumin
(indian curry spice), gingko biloba
 estrogen seems to slightly ↑ risk
drugs in development: vaccine approaches,
amyloid binding drugs (Alzamet), secretase
inhibitors that inhibit amyloid generation
Alzheimer’s is a progressive and irreversible
disorder. There is no cure but a major approach to
the treatment of AD has involved attempts to
augment the cholinergic function of the brain
Early approach was the use of precursors of
acetylcholine synthesis, e.g. choline chloride and
phosphatidyl choline (lecithin)-they were well
tolerated but have failed to demonstrate any
clinically significant efficacy.
A more successful strategy is the use of
approved AChE inhibitors for treatment of AD are
Rivastigmine and
Because of
the significant side-effect profile,
tacrine is not widely used in clinical practice.
Presynaptic neuron
Acetylcholine (Ach)
Presynaptic Knob
Synaptic gap
Synaptic Cleft
Postsynaptic Knob
Postsynaptic neuron
Presynaptic neuron
Acetylcholine (Ach)
Synaptic gap
Postsynaptic neuron
Role of AChE in synaptic gap
Presynaptic neuron
Acetylcholine (Ach)
Postsynaptic neuron
Mechanism of action of AChE inhibitor
A long acting cholinesterase inhibitor and
muscarine modulator, was the first drug
shown to have any benefit in AD.
Tacrine is orally active, enters the central
nervious system readily and has a
duration of efffect of 6-8 hours.
Tacrine blocks both acetylcholinesterase
and butyrylcholinesterase and has
complex inhibitory effect on several
muscarinic and nicotinic cholinoreceptor.
The drug apparently increases the release
of acetylcholine from cholinergic nerve
ending as well.
Tacrine may also have inhibitory effect on
MAO, decrease the release of GABA and
increase release of epinephrine, dopamine
and serotonin from nerve ending.
Although the evidence for benefit from
cholinesterase inhibitors appears to be
robust, the effect is very modest, at best,
delays further progression of cognitive
Adverse effect of Tacrine..
Nausia and vomiting – common
Hepatic toxicity-potentially dangeriousreversible increase in serum levels of
aspartate and aminotransferase of
sufficient magnititude- 40-50% treatment
Hepatocellular necrosis with jaundice has
been reported.
Donepezil is a selecive inhibitor of AChE and
produces modest improvements in cognitive
scores in AD patients. It has a long half-life,
allowing once-daily dosing
Rivastigmine and Galantamine
are dosed twice daily and produce a similar degree
of cognitive improvement
Side-effects are transient and dose dependant and
Vomiting and Insomnia
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