ALZHEIMER’S DISEASE
Presented by
Hong-An Nguyen
Medicinal Chemistry
April 28, 2009
OVERVIEW
I.
What is Alzheimer’s disease (AD)?
A. What is the prevalence of AD?
B. What are the symptoms?
C. How is AD diagnosed?
II.
III.
IV.
What is responsible for AD?
What are the approved current treatment?
Current research projects
A DISEASE OF AGING
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Alzheimer’s disease (AD) is
an irreversible, progressive
brain disease that slowly
destroys memory and
thinking skills, and
eventually even the ability to
carry out the simplest tasks.
Alzheimer’s disease is the
most common cause of
dementia among the elderly.
AD’s first symptoms usually
manifest after the age of 60.
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Dementia involves the loss of
cognitive functioning such as
thinking, remembering, and
reasoning, to such an extent
that it interferes with a
person’s daily life and
activities.
WILLIAM UTERMOHLEN’S SELF-PORTRAITS
CHRONICLING THE DESCENT INTO
ALZHEIMER’S
STATISTICS OF AD
AD currently affects 12million people worldwide
(4.5 million in America)
 This number is likely to triple with the aging of
the baby-boom generation by 2050.
 The prevalence rate for AD is about 7% for
individuals aged 65 or more, and the risk doubles
every 5 years after age 65.

THREE STAGES OF ALZHEIMER’S DISEASE
SEVEN EARLY SIGNS OF ALZHEIMER’S
DISEASE

The National Institute on Aging posted seven early
warnings of possible development of AD on their
website to educate the public and facilitate early
diagnostics:
1. Asking the same question over and over again.
2. Constantly repeating the same story, word for word.
3. Forgetting activities that were routine, such as cooking
or playing cards.
4. Losing one's ability to manage critical activities such as
managing finances and paying bills.
5. Getting lost in familiar surroundings, or misplacing
household objects.
6. Neglecting personal hygiene while insisting that they
were clean.
7. Relying on someone else to decide and respond on
issues they normally handled themselves.
MILD STAGE
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As AD progresses, memory loss continues and
changes in other cognitive abilities appear.
Symptoms in this stage can include:
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getting lost
trouble handling money and paying bills
repeating questions
taking longer than before to complete normal daily
tasks
poor judgment
losing things or misplacing them in odd places
mood and personality changes
In most people with AD, symptoms first appear
after age 60. AD is often diagnosed at this stage.
MODERATE STAGE
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In moderate AD, damage occurs in areas of the
brain that control language, reasoning, sensory
processing, and conscious thought. Symptoms
may include:
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increased memory loss and confusion
problems recognizing family and friends
inability to learn new things
difficulty carrying out tasks that involve multiple
steps (such as getting dressed)
problems coping with new situations
delusions and paranoia
impulsive behavior
ADVANCED STAGE
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People with severe AD cannot communicate and are
completely dependent on others for their care. Near
the end, the person with AD may be in bed most or all
of the time. Their symptoms often include:
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inability to recognize oneself or family
inability to communicate
weight loss
seizures
skin infections
difficulty swallowing
groaning, moaning, or grunting
increased sleeping
lack of control of bowel and bladder
The most frequent cause of death for people with AD
is aspiration pneumonia. This type of pneumonia
develops when a person cannot swallow properly and
takes food or liquids into the lungs instead of air.
DIAGNOSING ALZHEIMER’S DISEASE
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The only definitive way to confirm AD is with the autopsy of the brain.

However, several useful diagnostic methods have been developed.
WHAT CAUSES ALZHEIMER’S
DISEASE?
Scientists have not yet fully ascertained the
cause of AD. However, studies have shown that
AD arises from a combination of complex series of
events taking place in the brain, including
genetic, environmental, and lifestyle factors.
 Examination of the brains of AD patients has
revealed deposits of the amyloid β protein (Aβ)
known as senile plaques and the microtubuleassociated protein, Tau, known as
neurofibrillary tangles (NFT) in the brain.
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AMYLOID BETA PROTEIN (AB)
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Some cases of early-onset AD,
called familial AD (FAD), are
inherited. FAD is caused by a
number of different gene mutations
on chromosomes 21, 14, and 1, and
each of these mutations causes
abnormal proteins to be formed.
Mutations on chromosome 21 cause
the formation of abnormal amyloid
precursor protein (APP).
Each of these mutations causes an
increased amount of the betaamyloid protein to be formed. Betaamyloid, is formed from APP.
Aβ is formed after sequential
cleavage of the amyloid precursor
protein, a transmembrane
glycoprotein of undetermined
function. APP can be processed by
α-, β- and γ-secretases; Aβ protein is
generated by successive action of
the β and γ secretases
NEUROFIBRILLARY TANGLES (NFT)
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Neurofibrillary tangles are pathological protein
aggregates found within neurons in cases of
Alzheimer's disease. Tangles are formed by
hyperphosphorylation of a microtubule associated protein known as tau, causing it to
aggregate in an insoluble form.
FORMATION OF TAU TANGLES
APOLIPOPROTEIN E (APOE)
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Apolipoprotein E
(APOE) found on
chromosome 19 appears
to be a predisposing
genetic risk factor for
the late on-set of AD –
the most typical AD.
APOE helps carry
cholesterol in the
bloodstream.
APOE comes in several
different forms, or
alleles. Three forms—
APOE ε2, APOE ε3, and
APOE ε4—occur most
frequently.
TREATMENT OF ALZHEIMER’S DISEASE
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Mild to Moderate AD

cholinesterase inhibitors
may help delay or prevent
symptoms from becoming
worse for a limited time
and may help control some
behavioral symptoms
 Razadyne®
(galantamine, formerly
known as Reminyl®)
 Exelon® (rivastigmine)
 Aricept® (donepezil)
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Moderate to Severe AD
Namenda®
(memantine), an Nmethyl D-aspartate
(NMDA) antagonist.
 This drug’s main effect
is to delay progression of
some of the symptoms of
moderate to severe AD
 It may allow patients to
maintain certain daily
functions a little longer
than they would without
the medication
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RAZADYNE® (GALANTAMINE)
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Galantamine
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A competitive and reversible
inhibitor of
acetylcholinesterase.
It increases the concentration of
acetylcholine through reversible
inhibition of its hydrolysis by
cholinesterase
Absorption of galantamine is
rapid and complete and shows
linear pharmacokinetics.
It is well absorbed with
absolute oral bioavailability
between 80 and 100%. It has a
half-life of 7 hours.
It has not shown to alter the
underlying dementia process.
EXELON® (RIVASTIGMINE)
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Rivastigmine is a
cholinesterase inhibitor
that inhibits both
butyrylcholinesterase
and
acetylcholinesterase.
When given orally,
bioavailability is about
40% in the 3 mg dose.
The compound can cross
the blood-brain barrier.
ARICEPT® (DONEPEZIL)
The most widely used
drug for AD.
 the only treatment
approved by the FDA
for all stages of AD.
 100% bioavailability.
 Can cross the bloodbrain barrier.
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NAMENDA® (MEMANTINE)
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Acting on the
glutamatergic system by
blocking NMDA glutamate
receptors.
Blocks the toxic effects
associated with excess
glutamate and regulates
glutamate activation.
A dysfunction of
glutamatergic
neurotransmission is
thought to be involved in
the etiology of AD.
THE SEARCH FOR NEW TREATMENTS
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Causes of AD are still being actively researched.
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In the January 14, 2007, online Nature Genetics,
researchers described results of a study implicating the
gene SORL1 in late-onset Alzheimer's disease. The gene,
also known as SORLA (sortilin-related, low-density
lipoprotein receptor class A repeat-containing protein).
Researchers began to look into protein patterns in
order to help elucidate the causes of AD and come up
with new therapeutic treatment. In an article
appearing October 15, 2007, in the online Nature
Medicine, scientists reported to have studied 120
proteins involved in cell-to-cell communication,
looking for patterns that differed between people with
and without Alzheimer's.
SUMMARY OF ALZHEIMER’S DISEASE DRUGS
REFERENCES
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Brunton, Lazo, Parker. “Goodman & Gilman’s The Pharmacological Basis of
Therapeutics”, 11th ed. Chapter 20: Treatment of Central Nervous System
Degenerative Disorders by David G. Standaert and Anne B Young. 538-540.
National Institute on Aging. “Unraveling the Mystery of Alzheimer’s Disease”. Apr 20,
2009.
<http://www.nia.nih.gov/NR/rdonlyres/0FA2EE06-0074-4C45-BAA334D56170EB8B/0/Unraveling_final.pdf>.
Kumar Sambamurti, K. S. Jagannatha Rao1, Miguel A. Pappoll. “Frontiers in the
pathogenesis of Alzheimer’s disease”. Indian J Psychiatry 51: Supplement,
January 2009.
National Institute on Aging. “Alzheimer’s disease medications fact sheet”. Apr 20, 2009
< http://www.nia.nih.gov/NR/rdonlyres/5178456B-4E16-4A71-A70446637C6FE61B/11938/84206ADEARFactsheetMedicationsFINAL09FE B11.pdf>.
http://www.nia.nih.gov/Alzheimers/AlzheimersInformation/Causes/
http://www.realmentalhealth.com/medications/razadyne.asp#Drug
http://en.wikipedia.org/wiki/Rivastigmine
http://en.wikipedia.org/wiki/Galantamine
http://en.wikipedia.org/wiki/Donepezil
http://en.wikipedia.org/wiki/Mementine
http://www.webmd.com/alzheimers/guide/treatment-overview
http://www.webmd.com/alzheimers/guide/treatment-overview
http://www.alz.org/alzheimers_disease_research_ad.asp#Research