Alzheimers Disease

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Alzheimers Disease

• Progressive neurodegenerative disorder
• Profound cognitive and Behavioural impairments
• Cell losses in multiple brain regions
• Neurotransmitter and peptidergic abnormalities

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Symptoms

• The seven warning signs of Alzheimers disease
  are
• 1. Asking the same question over and over again.
• 2. Repeating the same story, word for word, again
  and again.
• 3. Forgetting how to cook, or how to make
  repairs, or how to play cards activities that
  were previously done with ease and regularity.
• 4. Losing ones ability to pay bills or balance
  ones checkbook.
• 5. Getting lost in familiar surroundings, or
  misplacing household objects.
• 6. Neglecting to bathe, or wearing the same
  clothes over and over again, while insisting that
  they have taken a bath or that their clothes are
  still clean.
• 7. Relying on someone else, such as a spouse, to
  make decisions or answer questions they
  previously would have handled themselves.

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Symptoms of AD

• Symptoms of AD similar to dementia caused by
  multi-infarct dementia.
• Distinct from mild cognitive impairment (MCI)
  associated with age.
• Distinct from fronto-cortical dementia

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Symptoms of AD

• confusion
• disturbances in short-term memory
• problems with attention and spatial orientation
• personality changes
• language difficulties
• unexplained mood swings

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Stage 1 Early in the illness, less energy and
spontaneity, though often no one notices anything
unusual. They exhibit minor memory loss and mood
swings, and are slow to learn and react. After a
while they start to shy away from anything new
and prefer the familiar. Memory loss begins to
affect job performance. The patient is confused,
gets lost easily, and exercises poor judgment.
Stage 2 In this stage, the Alzheimer's victim
can still perform tasks independently, but may
need assistance with more complicated activities.
Speech and understanding become slower, lose
their train of thought in mid-sentence. They may
also get lost while travelling or forget to pay
bills. As Alzheimer's victims become aware of
this loss of control, they may become depressed,
irritable and restless. The distant past may be
recalled, while recent events are difficult to
remember. Advancing Alzheimer's has affected the
victim's ability to comprehend where they are,
the day and the time. As the Alzheimer's victims
mind continues to slip away, the patient may
invent words and not recognize familiar
faces. Stage 3 During the final stage, patients
lose the ability to chew and swallow. The very
essence of the person is vanishing. Memory is now
very poor and no one is recognizable. Patients
lose bowel and bladder control, and eventually
need constant care. They become vulnerable to
pneumonia, infection and other illnesses.
Respiratory problems worsen, particularly when
the patient becomes bedridden. This terminal
stage eventually leads to death.  
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Histopathological Features

• Neurofibrillary Tangles and helical filaments-
  pairs of filaments wound around each other in a
  helical arrangement Composed mainly of abnormal
  tau but also immunoreactive for a number of other
  substances
• Amyloid plaques 1)neuritic plaques-dystrophic
  and degenerating neuronal processes.large bulbous
  structures 2)Diffuse plaques contain B-amyloid
  protein fibres and some unstructured
  amyloid-earliest 3)Burned out plaques-dense
  amyloid core

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Alzheimer Brain Atrophy
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Hallmarks of Alzheimer's disease include neuritic
plaques, (outside neurons), and neurofibrillary
tangles (inside neurons).
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Neurofibrillary Tangles
                                                
                                          
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Alzheimers Brain PET study
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Preclinical AD

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Stages of Disease Progression
Pre-clinical
Late -stage
Early -stage
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Causes of AD

• Age- number of people with disease doubles every
  5 years after 65
• Family History specific genetic mutations
• Apolipoprotein E

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2 Forms of AD

• 1. Familial known genetic mutations in a number
  of families (lt10 cases)
• 2. Sporadic- Apolipoprotein only known risk
  factor

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Familial AD

• Familial AD (FAD) is a rare form of AD, affecting
  less than 10 percent of AD patients.
• All FAD is early-onset, meaning the disease
  develops before age 65. It is caused by gene
  mutations on chromosomes 1 (presenelin 1)
• 14 (presenelin 2)
• 21 (Amyloid precursor protein)
• Even if one of these mutated genes is inherited
  from a parent, the person will almost always
  develop early-onset AD.
• This inheritance pattern is referred to as
  autosomal dominant inheritance. In other words,
  all offspring in the same generation have a 50/50
  chance of developing FAD if one of their parents
  had it.

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Genes involved in AD

• Familial AD- early onset
• Sporadic- late onset
• APOE only one associated with late onset
• 3 alleles of the APOE gene 2,3,4
• APOE4 increases risk for late onset
• APOE2 protective effect
• Normally involved in transport of cholesterol in
  blood
• ApoE and amyloid link Normally beta amyloid
  is soluble, but when the apoE4 protein latches on
  to it, the amyloid becomes insoluble. This may
  mean that it is more likely to be deposited in
  plaques. Studies of brain tissue suggest that
  apoE4 increases deposits of beta amyloid and that
  it directly regulates the APP protein from which
  beta amyloid is formed.

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Apolipoprotein and AD

• Alleles - different forms of the same gene. Two
  or more alleles can shape each human trait. Each
  person receives two alleles, one from each
  parent. This combination is one factor among many
  that influences a variety of processes in the
  body.
• ApoE Gene - a gene on chromosome 19 involved in
  making apoE, a substance that helps carry
  cholesterol in the bloodstream. ApoE is
  considered a "susceptibility" gene for AD and
  appears to influence the age of onset of the
  disease. However, it is not the sole cause of AD.
  No cause and effect relationship exists between a
  person's apoE status and the development of AD.

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ApoE and AD

• On chromosome 19, the apolipoprotein E (apoE)
  gene has three common forms or alleles E2, E3,
  and E4. Thus, the possible combinations in one
  person are E2/2, E2/3, E2/4, E3/3, E3/4, or E4/4.
  
• Having one or two copies of the E4 allele
  increases a person's risk of getting AD. That is,
  having the E4 allele is a risk factor for AD, but
  it does not mean that AD is certain.
• Some people with two copies of the E4 allele (the
  highest risk group) do not develop the disease
  while others with no E4s do.
• The rarer E2 allele appears to be associated with
  a lower risk of AD. The E3 allele is the most
  common form found in the general population and
  may play a neutral role in AD.
• The exact degree of risk of AD for any given
  person cannot be determined based on apoE
  status.Can be tested in a blood test.

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ApoE and AD

• In a research setting, apoE testing may be used
  to identify study volunteers who may be at a
  higher risk of getting AD. In this way,
  researchers can look for early brain changes in
  some patients.
• ApoE test is useful for studying AD risk in large
  groups of people but not for determining one
  person's individual risk. Predictive screening in
  otherwise healthy people will be useful if an
  accurate/reliable test is developed and effective
  ways to treat or prevent AD are available.
• (our study)

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Summary genes involved in AD(adapted from Lendon
Craddock (2001) TINS, 24,557-559)
Gene Location APP 21 Goate et al,
(1991) APOE (susceptibility) 19 Corder
(1993) PS-1 14 Rogaev et al
(1995) PS-2 1 Levey-Lahad et al
(1995) APPamyloid precursor protein APOEapolip
oprotein PSpresenelin
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Amyloid Hypothesis and Alzheimers Disease

• AD characterised by amyloid plaques which contain
  mainly aggregated AB peptide derived from amyloid
  precursor protein (APP)
• Mutations at or near to chromosome 21 (which
  contains the APP gene) have been discovered in
  familial AD
• Downes syndrome people who have an extra copy of
  chromosome 21 invariably develop AD

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Nun study
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Nun Study

• Snowden et al, Univ. Kentucky
• 678 sisters of Notre Dame aged 75-103
• Tested annually on cognitive functioning and
  health and post mortem plaques tangles
• Individuals with overt dementia had signs of
  infarct (stroke) in addition to plaques and
  tangles
• Prevalence of dementia in those with AD (ie
  abundant plaques and tangles)
• 93 with infarcts in areas basal ganglia,thalmus
• 57 without infarcts

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Fronto-temporal Dementia
FTD primarily affects the frontal and anterior
temporal lobes of the brain. These areas control
executive functions such as reasoning,
personality, social behavior, movement, speech,
language, and certain aspects of memory.
Develops between the ages of 35 and 75.
Patients generally live with the disease for 2 to
10 years after diagnosis. FTD appears to be
quite rare researchers believe that FTD accounts
for perhaps 3 percent of all dementia cases.
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Fronto-temporal Dementia

• Strong genetic component, for in 20-40 percent
  of the cases, the person had a family history of
  dementia.
• 1998 discovered that a mutation in the tau gene
  causes a form of FTD called frontotemporal
  dementia with parkinsonism linked to chromosome
  17 (FTDP-17).

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Cholinergic Hypothesis

• Bartus (1982) cholinergic hypothesis of
  geriatric memory dysfunction
• 1) significant functional disturbances occur in
  brains of aged and esp. demented people
• 2)These disturbances play an important role in
  the memory loss and related cognitive problems
  asociated with old age and dementia
• 3)Restoration of cholinergic function may
  significantly reduce the severity of cognitive
  loss

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Cholinergic Hypothesis-Evidence

• Correlation between severity of dementia, and
  cholineacetyltransferase activity (chAT) and cell
  loss in cholinergic cell containing area nucleus
  basalis Meynert and cognitive impairment
• Cholinergic antagonists induce amnesia in people
  and animals

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Treatment of AD

• Distinction between palliative and
  preventative.
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• Current treatment is Donepezil (Aricept).
• Acetylcholinesterase inhibitor
• Prototype ache inhibitors physostigmine and
  tacrine improves cognitive function in healthy
  volunteers.
• Minimal efficacy side effects

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Treatment of AD -new Directions

• Statins to lower cholesterol
• Anti-inflammatory drugs e.g. ibuprofen,aspirin
• Targetting amyloid deposition

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Modelling Aspects of AD in animals

• Selective lesion of neurochemical pathways
• Cholinergic antagonists
• Aged animals
• Transgenic animals

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AD animal models before transgenic technology

• Neurotoxic/electrolytic lesion of monoaminergic
  neurotransmitter systems esp. cholinergic
• Acute pharmacological challenges typically using
  muscarinic cholinergic antagonists
• Normal ageing,chronic alcohol/ischaemia

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Nucleus basalis Magnocellularis Lesions

• NBM lesions disrupt passive avoidance,spatial
  alternation,radial arm maze,DMTS. Concomitant
  decrease in chAT activity
• Sepcificity of neurotoxins used critical
• Dunnett (1989) disruption of conditioned
  discrimination task with ibotenic acid but not
  quisqualic acid
• Behavioural recovery with repeated training in
  water amze with no recovery in cortical chAT

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Lesion of Forebrain Cholinergic Neurons   IgG
monoclonal antibody to nerve growth factor
coupled to a ribosome inactivating cytotoxin
saporin. Antibody targets cholinergic sites which
possess ngf receptors but not neighbouring
non-cholinergic sites that do not contain these
receptors.   Summary of extent and location of
cholinergic damage produced by 192 IgG-saporin
lesion compared to other neurotoxins    
      Saporin spares subpopulation of cholinergic
receptors major cholinergic input to the
basolateral amygdala.    
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APP Transgenic mice

• NSE-APP751 (Moran et al 1995)-behaviour
  abnormalities, diffuse plaques
• PDGF-APP751(Beyreuther)No histopathology
  behavioural abnormalities no cog changes
• Montreal mice (Nalbantoglu,1997)amyloid
  reactivity,increased cell loss in
  hippocampus,loss of spatial learning
• Athena mouse (Games,1995) An APP minigene
  construct with familial mutation. Amyloid gliosis
  no behavioural abnormalities.
• Minnesota mouse (Hsaio,1996) Prion protein gene
  promotor to drive APP swedish mutation

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Reading List
Janus, C. Westway,D. (2001) Transgenic mouse
models of Alzheimers Disease. Physiology and
Behaviour, vol., 73, 5 873-886.   Hock, B.J.
Lamb, B.T. (2001) Transgenic mouse models of
Alzheimers Disease. Trends in Genetics, vol.17,
issue 10, s7-s12.   Auls, D.S., Kornecook, T.J.,
Bastianetto, S., Quirion,R. (2003) Alzheiemrs
Disease and the basal forebrain cholinergic
system relations to B-amyloid peptidescognition
and treatment. Progress in Neurobiology, vol. 68,
issue 3 , pp 209-245.   These can be read in full
text on www.sciencedirect.com