Sree Vidyanikethan College Of Pharmacy.
There are many diseases, which haunt human
beings with severe morbidity and mortality in
spite of advancement of medicine and
Few diseases were controlled with the
discovery of newer drugs and few are still
Alzheimer's disease, which cripples the
elderly people with dementia and increases
the burden of the family and the government
is one of them.
Alzheimer's disease (AD) is the most common
form of dementia, a neurologic disease
characterized by loss of mental ability severe
enough to interfere with normal activities of
daily living, lasting at least six months, and
not present from birth. AD usually occurs in
old age, and is marked by a decline in
cognitive functions such as remembering,
reasoning, and planning.
Initially, dementia is manifested by barely noticeable
memory deficits. Eventually, the memory loss becomes
more severe until it is incapacitating.
Other symptoms such as confusion, the inability to
articulate words correctly, and hallucinations occur with
Affected individuals are also likely to develop seizures,
hypertonicity (increased muscle movements), and
Between two and four million Americans have AD; that
number is expected to grow to as many as 14 million by the
middle of the 21st century as the population as a whole ages.
Estimated 4 million cases in US (2000)
(2000 - 46 million individuals over 60 y/o)
Estimated 500,000 new cases per year
Increase with age (prevalence)
› 1% of 60 - 65 (10.7m) = 107,000
› 2% of 65 - 70 ( 9.4m) = 188,000
› 4% of 70 - 75 ( 8.7m) = 350,000
› 8% of 75 - 80 ( 7.4m) = 595,000
› 16% of 80 - 85 ( 5.0m) = 800,000
U.S. mortality rate by age
1999 CDC / 2000 census
1.0000 Alzheimer incidence
0 10 20 30 40 50 60 70 80 90 100
The condition was first described in 1906 by Alois
Alzheimer, a German physician.
Alzheimer characterized two abnormal
structures in the brain
and neurofibrillary tangles.
Although there are several known causes of
Alzheimer disease, about 75% of cases are
sporadic and occur without a clear cause.
Scientists assume that these cases are due to a
combination of unknown genetic predisposing
factors and environmental exposures.
Need to get elderly, clinicians interested in screening for
Need test to screen patients for Alzheimer’s disease
Test needs to be on multiple platforms:
Best if computerized for rapid, objective assessment
World-Wide Web – based testing,
Test needs to be very brief (about 1-minute)
Multiple test forms needed so it can be repeated often
Screening should be done yearly after age 50, and repeated
every 3 months for individuals over 65 years of age or with
Any change over time needs to be detected
The test should be free
Need program to handle positive screens sensitively and
New test to screen patients for AD:
World-Wide Web – based testing,
Determine level of ability / impairment
Test takes about 1-minute
Test can be repeated often (e.g., quarterly)
Any change over time can be detected
Free test is at: www.medafile.com
FUNCTIONAL BRAIN IMAGING (SPECT, PET – Medicare will
pay special cases)
EEG, Evoked Potentials (P300)
REACTION TIMES (slowed in the elderly, especially
when complex response is required.
CSF ANALYSIS - ROUTINE STUDIES
ELEVATED TAU (future possible)
DECREASED AMYLOID (future possible)
HEAVY METAL SCREEN (24 hr urine)
APO-LIPOPROTEIN-E (for supporting dx)
AUTOSOMAL DOMINANT (young onset)
Acetylcholine (Ach) is responsible for learning and memory
Ach is found abundantly in Hippocampus (memory store) and
It was thought at that time that Alzheimer's disease might disrupt
the synthesis of Ach.
Alzheimer's disease might triggers the over- production of the
enzyme that destroys Ach - Acetyl cholinesterase enzyme .
Apart from Ach, other neurotransmitters implicated are serotonin,
noradrenaline, and dopamine.
Noradrenaline, dopamine deficits are responsible for sensory
disturbances, aggressive behavior.
II) Cholinergic hypothesis
Degeneration of Cholinergic neurons of Hippocampus and
cerebral cortex in Alzheimer's disease leads to deficiency in Ach,
which is responsible for loss of cognition, behavioral changes,
III) Amyloid precursor protein (APP)
APP - normal protein produced by healthy neurons
Responsible for growth and maintenance of neurons
Enzymes like a, b, g secretases cut APP to form A-beta
protein ( which is insoluble , shorter and sticker)
A-beta protein (insoluble, sticker)
Fibrils (insoluble) Cluster and expand to form plaques.
Displaces or kills brain cells
Damages cell's interiors
Triggers an inflammatory response.
To fight this inflammatory response, brain generates
toxic free radicals .
V) Neurofibrillary tangles
Neurons branch off at te ends forming neuritis.
Neuritis made up of skeletal structures called
Microtubule gives shape to neuron, transport nutrients,
Microtubules are glued together by Tau Proteins .
In healthy brain, Tau is firmly glued to the microtubules.
In Alzheimer's disease, Tau proteins are destroyed by
enzymes, leading to formation of Neurofibillary tangles.
Without Tau proteins, neuronal cells shrinks,
disintegrates and die.
Evidence has boiled down to chromosomes 14, 19, 21
APOLIPO for Alzheimer's disease Protein E4 (Apo E4)
Apo E4 leads to the insolubility of A- beta protein,
Familial AD (onset < 60 y/o) (<5%)
all known autosomal dominant genes relate to b-amyloid
Presenilin I, II (ch 14, 1)
APP (ch 21)
Non-familial (late onset)
Clinical studies suggest 40 – 50% due to e4
If e2 is considered, may be 95% of causation
Population studies suggest 10 – 20% cause
Evolution over last 300,000 to 200,000 years
At least 20 other genes suspected of relating to AD
Of all persons with Alzheimer disease, up to 25% of cases are
thought to be part of a familial-based inheritance pattern.
In general, these forms of Alzheimer disease are inherited as
an autosomal dominant disorder, meaning that affected
individuals have a 50% chance of passing on the mutated
gene to their offspring.
There is a late-onset familial form (AD2), three early-onset
familial forms (AD1, AD3, AD4), and a form of Alzheimer
disease associated with Down syndrome.
AD1 ---10–15% of earlyonset Alzheimer disease and involves a
protein called presenilin 1 that has a mutation in the gene
that encodes it called PSEN1, which is found on chromosome
AD3 ---- 20–70% of the early-onset familial form and is
caused by mutations in APP found on chromosome 21, which
encodes a protein called amyloid beta A4.
AD4 is extremely rare and is caused by mutations in PSEN2,
localized to chromosome 1, and encodes a protein called
GenT %pop %AD #pop #AD risk If all US
E2/2 1% 0.1% 0.5M .004M 0.8% .4 M
E2/3 12 % 4% 5.5M .18M 3.2% 1.5 M
E3/3 60% 35% 27.6M 1.4M 5.1% 2.3 M
E3/4 21% 42% 9.6M 1.7M 18% 8.2 M
E4/4 2% 16% .9M .6M 67% 30.7M
JW Ashford, MD PhD, 2003
Less than 1% of all cases of Alzheimer disease--
chromosomal defect called trisomy 21 (also
known as Down syndrome).
This occurs when there are three copies of genes
found on chromosome 21.These individuals
usually develop Alzheimer disease after the age
The APP gene, which encodes the amyloid
precursor protein and is implicated in the
pathogenesis of Alzheimer disease, is localized
to chromosome 21; it is felt that people with
Down syndrome overproduce this protein,
resulting in its accumulation in the brain. The
excess protein is thought to cause the disease.
People with AD are also often depressed or
anxious, and may suffer from sleeplessness,
poor nutrition, and general poor health. It is
important for the person with AD to eat well
and continue to exercise. Diet and
VITAMIN E. Studies have shown that AD
patients have lower blood levels of vitamin E
THIAMINE (VITAMIN B1). COBALAMIN (VITAMIN
B12). ACETYL-L-CARNITINE. MELATONIN.
Melatonin is a hormone that helps to regulate
mood and sleep cycles.
GINKGO. Ginkgo, the extract from the Ginkgo
biloba tree is the most commonly used
herbal treatment for AD.
CLUBMOSS. Huperzine A is a compound
isolated from clubmoss (Huperzia serrata).
The two drugs approved for AD are tacrine
hydrochloride (Cognex) and donepezil hydrochloride
(Aricept), increase the brain levels of the
neurotransmitter acetylcholine, thereby increasing
the communication ability of the remaining neurons.
Preliminary studies have also suggested a reduced
risk for developing AD in older people who regularly
use nonsteroidal anti-inflammatory drugs (NSAIDs),
including aspirin, ibuprofen (Advil), and naproxen
(Aleve), although not acetaminophen.
Selegiline, a drug used in the treatment of Parkinson's
disease, appears to slow the development of AD.
AChEIs may improve, maintain, or slow the decline of
cognitive, behavioral, and functional performance in
patients with mild-to-moderate AD
Delay of treatment leads to loss of potential benefit
AChEIs may delay nursing home placement over 20
months, and potentially much more when started early.
AChEIs have demonstrated consistent efficacy and
safety in maintaining cognitive function, as measured
by ADAS-cog in patients with mild-to-moderate AD for
up to 1 year – relative to placebo!!
Donepezil1 38 weeks
Rivastigmine2 38–42 weeks
Galantamine3 52 weeks (25-30% better)
Increases amount of acetylcholine available in synaptic
cleft by inhibiting breakdown of acetylcholine
By modulating activity at nicotinic receptors, it may
increase release of acetylcholine from surviving
presynaptic nerve terminals
Combination action may diminish cholinesterase
supersensitivity from developing, prolonging the benefit.
May provide greatest delay of illness progression
May require increase of dose after patient declines below
initial baseline, to maintain benefit for longer term.
Half-life: 7 hours
Low (18%) plasma protein binding
Hepatic metabolism via multiple pathways,
primarily CYP2D6 and CYP3A4
Simple, one-step dose escalation
8 mg/day starting dose
for 4 weeks (4 mg bid)
16 mg/day maintenance dose
for at least 4 weeks (8 mg bid)
The flexibility to increase to 24 mg/day
(12 mg bid) – should try after 12 weeks if further benefit sought
Taken preferably with morning and evening meals
Later, better with morning meal, mid-afternoon snack.
(Avoid nocturnal cholinergic activation!!)
Available in 4-mg, 8-mg, and 12-mg tablets and
oral solution (4 mg/mL)
Inspite of medicines the disease is incurable
completely, The field of pharmaceutical
Biotechnology called as Gene Therapy gives
promising results for alzheimers.
Gene therapy is a technique for correcting
defective genes for disease development.
Now the field of biotechnology started focusing
disease on its genetic level and was very much
stressed towards a particular gene that is
responsible for the disease development.
Gene therapy is a technique for introducing the
genetic material of a gene in a patient that
lacks that gene because of a mutation.
But actually gene therapy works in the
1. A "normal" gene is inserted into the
genome to replace an "abnormal," disease-
2. A carrier molecule called a vector must
be used to deliver the therapeutic gene to
the patient's target cells.
3. The most common vector is a virus that
has been genetically altered to carry
normal human DNA
University Hospitals Case Medical Center is
one of 12 sites conducting the first Phase 2
clinical trial of a gene therapy for
Alzheimer's disease (AD). The study uses a
viral-based gene transfer system called CERE-
University Hospitals (UH) is the only site in
the Midwest for the study.
During the study, CERE-110 will be injected by
a neurosurgeon into the nucleus basalis of
Meynert, an area of the brain where nerve
cells die in patients with AD.
The first gene therapy for alzheimers among
12 centers was conducted at Georgetown's
Georgetown University Medical Center in
Memory Disorders Program.
The phase II study examined the safety and
possible benefits of CERE-110. CERE-110
contains a gene and is injected during
surgery into a part of the brain affected by
Alzheimer's disease. The gene will instruct
brain cells to produce more of a protein,
called Nerve Growth Factor or NGF, which
helps nerve cells survive and function
properly. The transfer of this gene into the
brain is a medical technique called gene
Neurosurgeons at the University of California
in San Diego (UCSD) injected 2.5 million
genetically modified cells into a 60-year-old
woman's brain through a small hole drilled in
her skull. The procedure took 11 hours.
Scientists began by harvesting skin cells from
the woman. Then they inserted into these
skin cells the gene that directs the
production of a protein called nerve growth
factor (NGF). NGF is a naturally occurring
protein in normal brains.
One of its jobs is to keep brain cells alive by promoting
growth and survival (much like food helps us grow and
NGF helps the cholinergic system function properly. This
system includes nerve cells that produce the
neurotransmitter acetylcholine, a chemical signal the
brain needs to process information and to function
In the brain of an Alzheimer's patient, the cholinergic
cells stop making acetylcholine. Low acetylcholine levels
can cause problems with memory, emotions, and
The procedure carried out by insertion of the modified
skin cells into the nucleus basalis, a group of cells about
the size of your thumbnail at the base of the frontal lobe.
This area contains many cholinergic nerve cells. The cells
were injected only into the right side of the brain.
The available NGF synthesis stimulators are
a. Idebenone and
In WASHINGTON scientists reported that The
first attempt at gene therapy for Alzheimer’s
patients appeared to significantly delay
worsening of the disease in a few people who
have tested it so far.
Far more research is needed to see if the
experimental treatment, which requires a
form of brain surgery, really helps.
But if the approach pans out,
researchers say delivering protective
substances, called growth factors,
into a diseased brain holds the
potential to rescue some dying brain
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