alzheimers disease

							                                    BY
                     THANUJA BACHALA
                           M.PHARMACY
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
  therapeutics.
 Few diseases were controlled with the
  discovery of newer drugs and few are still
  uncontrollable.
 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
    varying degrees.
   Affected individuals are also likely to develop seizures,
    hypertonicity (increased muscle movements), and
    incontinence.

Etiology
         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
                                  Males
                                  Females
              1.0000              Alzheimer incidence

              0.1000
probability




              0.0100

              0.0010

              0.0001
                       0   10 20 30 40 50 60 70 80 90 100
                                         Age
   The condition was first described in 1906 by Alois
    Alzheimer, a German physician.

   Alzheimer      characterized        two   abnormal
    structures in the brain
               amyloid plaques
               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
    dementia
   Need test to screen patients for Alzheimer’s disease
   Test needs to be on multiple platforms:
     Doctor’s offices
     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
    (quarterly)
   Screening should be done yearly after age 50, and repeated
    every 3 months for individuals over 65 years of age or with
    concerns
   Any change over time needs to be detected
   The test should be free
   Need program to handle positive screens sensitively and
    efficiently.
 New    test to screen patients for AD:
     World-Wide Web – based testing,
     CD-distribution
     KIOSK administration

 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)

   GENOTYPING
       APO-LIPOPROTEIN-E (for supporting dx)
       AUTOSOMAL DOMINANT (young onset)
I) Neurotransmitters
   Acetylcholine (Ach) is responsible for learning and memory
   Ach is found abundantly in Hippocampus (memory store) and
    cerebral cortex
   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,
    mood disturbances.
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)
   A-beta folds
   Fibrils (insoluble) Cluster and expand to form plaques.

IV) 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
  Microtubules.
 Microtubule gives shape to neuron, transport nutrients,
  chemical messengers.
 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.
  VII) Genes:
 Evidence has boiled down to chromosomes 14, 19, 21
  APOLIPO for Alzheimer's disease Protein E4 (Apo E4)
  gene.
 Apo E4 leads to the insolubility of A- beta protein,
  forming Plaques.
 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)
    APOE
        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
    14.

   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
    presenilin 2.
       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
  of 40.
 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
  Supplements
 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.
 PHYTOESTROGENS.
 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.
Linear pharmacokinetics

    Bioavailability: 90%

    Half-life: 7 hours

    Low (18%) plasma protein binding

    Hepatic metabolism via multiple pathways,
     primarily CYP2D6 and CYP3A4

    Renal excretion
   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
 following ways
 1. A "normal" gene is inserted into the
 genome to replace an "abnormal," disease-
 causing gene.
 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-
  110.
 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
  therapy.
 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
    thrive).
   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
    normally.
    In the brain of an Alzheimer's patient, the cholinergic
    cells stop making acetylcholine. Low acetylcholine levels
    can cause problems with memory, emotions, and
    language.
   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
  as follows:
  a. Idebenone and
  b. Propentofylline
CONCLUSION:
 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
 cells
    Rogers SL et al. Eur Neuropsychopharmacol.
    2000;10:195-203.
   Farlow M et al. Eur Neurol. 2000;44:236-241.
   Raskind MA et al. Neurology. 2000;54:2261-2268.
   Diagnosis and Management of Alzheimer's Disease. 2nd
    edition, edited by Serge Gauthier. London: Martin Dunitz,
    1999.
   Luskin, Frederic M., Ellen M. DiNucci, Kathryn A. Newell, and
    William L. Haskell. "Complementary/Alternative Therapies in
    Select Populations: Elderly Persons." In
    Complementary/Alternative Medicine: An Evidence Based
    Approach. Edited by John W. Spencer and Joseph J. Jacobs.
    St. Louis: Mosby, 1999.
   Mace, Nancy L., and Peter V. Rabins. The 36-Hour Day. The
    John Hopkins University Press, 1995.