 Global prevalence 24 million predicted to double every 20
years to 2040
 5% over 65 years
 20% over 80 years
 Over 65...
Many causes but commonest are:
 Alzheimer’s Disease
 Vascular Dementia
 Lewy Body Dementia
 Alcohol related dementia
...
Dementia –
A general term for a group of disorders that cause
irreversible cognitive decline as a result of
biological dam...
 Alzheimer disease (AD) is the most common form of dementia and usually
occurs in old age.
 It is invariably fatal, gene...
 Neuropathology
◦ Alzheimer's disease is characterised by loss of neurons and
synapses in the cerebral cortex and certain...
Both amyloid plaques and neurofibrillary tangles are clearly visible by
microscopy in brains of those afflicted by AD.
◦ P...
 Biochemistry
 Outside neurons
◦ Enzymes act on the APP (amyloid precursor protein) and cut it into
fragments. The beta-...
 Biochemistry
 Inside neurons:
◦ In Alzheimer's disease, an abnormal aggregation of the tau protein
lead to the disinteg...
 Enzymes act on the APP (Amyloid precursor
protein) and cut it into fragments of protein,
one of which is called beta-amy...
 Early-onset Alzheimer's disease occurs in people age 30 to 60.
 Rare, representing less than 5 percent of all people wh...
 Secretase
◦ BACE1
 β-amyloid cleaving enzyme1
 This transmembrane aspartyl protease is directlly involved in
the cleav...
 Most cases of Alzheimer's are the late-onset form, which
develops after age 60.
 The causes include a combination of ge...
 APOE ε3, the most common allele, is believed to play
a neutral role in the disease—neither decreasing nor increasing
ris...
 Aβ amyloidosis
◦ Amyloid beta is a peptide of 39-43 amino acids
◦ Main constituent of amyloid plaques in the brains of A...
There are no established direct genetic causes for the more common
forms of vascular dementia
Some studies have reported...
 FTD often runs in families.
 About one third of people with it have a
family history.
 In 10–15% is inherited as a mut...
 The genetics of dementia with Lewy bodies
(DLB) is not well understood,.
 The symptoms of DLB overlap with those of
bot...
 People with Down's syndrome are at
particular risk of developing dementia.
 This is typically Alzheimer's disease, whic...
 Huntington's disease is a rare progressive
hereditary condition caused by a mutation
in a particular gene (Huntingtin).
...
 Indications:
 Anyone who is worried about inheriting a form of
dementia and who has a relative with the condition
 If ...
 Help genetic researchers understand the
disease better and so lead to improved
treatment
 Encourage someone to adopt a ...
However, genetic testing may create
problems, for the following reasons:
 A genetic defect cannot be repaired, .
 A gene...
It is anticipated that discoveries during the next
few year will lead to the design of new
mechanism-based on gene therapi...
Genetics of dementia
Genetics of dementia
Genetics of dementia
Genetics of dementia
Genetics of dementia
Genetics of dementia
Genetics of dementia
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Genetics of dementia

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Early-onset Alzheimer's disease occurs in people age 30 to 60.
Rare, representing less than 5 percent of all people who have Alzheimer's Inherited type known as familial Alzheimer's disease (FAD). It caused by mutations in at least 3 genes ( these Mutations increase the production of a Aβ42) :Most cases of Alzheimer's are the late-onset form, which develops after age 60.
The causes include a combination of genetic, environmental, and lifestyle factors .
the increase risk is related to the apolipoprotein E (APOE) found gene  on chromosome 19.
APOE contains the instructions for making a protein that helps carry cholesterol and other types of fat in the bloodstream. APOE comes in different forms, or alleles. Three forms—APOE ε2, APOE ε3, and APOE ε4—occur most frequently.
APOE ε2 is relatively rare and may provide some protection against the disease.
If Alzheimer's disease occurs in a person with this allele, it develops later in life than it would in someone with the APOE ε4 gene.

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Genetics of dementia

  1. 1.  Global prevalence 24 million predicted to double every 20 years to 2040  5% over 65 years  20% over 80 years  Over 65 years - prevalence doubles every 5 yrs  Annual incidence c. 9 / 1000 population
  2. 2. Many causes but commonest are:  Alzheimer’s Disease  Vascular Dementia  Lewy Body Dementia  Alcohol related dementia  Frontotemporal dementia Other forms of dementia include •Parkinson’s disease •Creutzfeldt-Jakob disease •Normal pressure hydrocephalus
  3. 3. Dementia – A general term for a group of disorders that cause irreversible cognitive decline as a result of biological damage to brain cells Alzheimer’s disease (AD) –the most common dementia, accounting for 50-70 percent of cases
  4. 4.  Alzheimer disease (AD) is the most common form of dementia and usually occurs in old age.  It is invariably fatal, generally within ten years of the first signs.  Normal aging involves forgetfulness but the early signs of AD include unusual memory loss. (remembering recent events and the names of people and things)  As the disease progresses the patient exhibits more serious problems. (subject to mood swings and unable to perform complex activities such as driving.)  In the latter stages they forget how to do simple things and then require full- time care.
  5. 5.  Neuropathology ◦ Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. ◦ This loss results in degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex. ◦ Reductions in the size of specific brain regions in patients as they progressed from mild cognitive impairment to Alzheimer's disease.
  6. 6. Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD. ◦ Plaques are dense, mostly insoluble deposits of amyloid-beta peptide and cellular material outside and around neurons. ◦ Tangles (neurofibrillary tangles) are aggregates of the microtubule- associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves.
  7. 7.  Biochemistry  Outside neurons ◦ Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of senile plaques in AD. ◦ AD has been identified as a protein misfolding disease, caused by accumulation of abnormally folded A-beta and tau proteins in the brain. ◦ Plaques are made up of small peptides, 39–43 amino acids, called beta-amyloid (also written as A-beta or Aβ).  fragment from a larger protein called APP, a transmembrane protein that penetrates through the neuron's membrane.  (APP: neuron growth, survival and post-injury repair)
  8. 8.  Biochemistry  Inside neurons: ◦ In Alzheimer's disease, an abnormal aggregation of the tau protein lead to the disintegration of microtubules in brain cells.  Tau protein(microtubule-associated protein) stabilizes the microtubules when phosphorylated.  In AD, tau becoming hyperphosphorylated; creating neurofibrillary tangles and disintegrating the neuron's transport system.
  9. 9.  Enzymes act on the APP (Amyloid precursor protein) and cut it into fragments of protein, one of which is called beta-amyloid and its crucial in the formation of senile plaques in Alzheimer
  10. 10.  Early-onset Alzheimer's disease occurs in people age 30 to 60.  Rare, representing less than 5 percent of all people who have Alzheimer's  Inherited type known as familial Alzheimer's disease (FAD).  It caused by mutations in at least 3 genes ( these Mutations increase the production of a Aβ42) :  PSEN1 - Presenilin 1 (PSEN1 located on chromosome 14) ◦ Mutations in this gene cause familial Alzheimer's type under 50 years old. ◦ This protein has been identified as part of the enzymatic complex that cleaves amyloid beta peptide from APP.  PSEN2 - Presenilin 2 (PSEN2 located on chromosome 1) ◦ The presenilin 2 gene is very similar in structure and function to PSEN1.  APP – Amyloid beta (A4) precursor protein ◦ Processing of the amyloid precursor protein ◦ Mutations to the amyloid beta A4 precursor protein (APP) located on the long arm of chromosome 21 causes familial Alzheimer disease.
  11. 11.  Secretase ◦ BACE1  β-amyloid cleaving enzyme1  This transmembrane aspartyl protease is directlly involved in the cleavage of APP at the sites of Aβ in APP. ◦ γ-secretase  This multiprotein catalytic complex includes PS1 and PS2; nicastrin (Nct), a type 1 transmembrane glycoprotein; and Aph- 1 and Pen-2, two multipass transmembrane protein. APP and PS families of proteins
  12. 12.  Most cases of Alzheimer's are the late-onset form, which develops after age 60.  The causes include a combination of genetic, environmental, and lifestyle factors .  the increase risk is related to the apolipoprotein E (APOE) found gene on chromosome 19.  APOE contains the instructions for making a protein that helps carry cholesterol and other types of fat in the bloodstream. APOE comes in different forms, or alleles. Three forms—APOE ε2, APOE ε3, and APOE ε4—occur most frequently.  APOE ε2 is relatively rare and may provide some protection against the disease.  If Alzheimer's disease occurs in a person with this allele, it develops later in life than it would in someone with the APOE ε4 gene.
  13. 13.  APOE ε3, the most common allele, is believed to play a neutral role in the disease—neither decreasing nor increasing risk.  APOE ε4 is present in about 25 to 30 percent of the population and in about 40 percent of all people with late-onset Alzheimer's.  People who develop Alzheimer's are more likely to have an APOE ε4 allele than people who do not develop the disease.  APOE ε4 is called a risk-factor gene because it increases a person's risk of developing the disease.  However, inheriting an APOE ε4 allele does not mean that a person will definitely develop Alzheimer's. Some people with one or two APOE ε4 alleles never get the disease, and others who develop Alzheimer's do not have any APOE ε4 alleles.
  14. 14.  Aβ amyloidosis ◦ Amyloid beta is a peptide of 39-43 amino acids ◦ Main constituent of amyloid plaques in the brains of Alzheimer’s disease patients. ◦ Aβ is proteolytically derived from a larger integral membrane protein, the amyloid precursor protein (APP).  AD-linked taupathies ◦ Taupathies are a class of neurodegenerative diseases resulting from the pathological aggregation of tau protein in so-called neurofibrillary tangles (NFT) in the human brain.
  15. 15. There are no established direct genetic causes for the more common forms of vascular dementia Some studies have reported links between APOE and vascular dementia  The most recent findings suggest that APOE ε4 is a risk factor for vascular dementia, but with weaker effects than for Alzheimer's disease. There are also known genes that contribute to some risk factors such as high cholesterol levels, high blood pressure and diabetes. Overall, the role of genes seems to be less significant . Some very rare forms of vascular dementia are caused by known simple genetic defects. For example, mutations in a gene called NOTCH3 cause a rare form of vascular dementia known as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL is inherited in a simple, single-gene pattern similar to early onset familial Alzheimer's disease.
  16. 16.  FTD often runs in families.  About one third of people with it have a family history.  In 10–15% is inherited as a mutation in a single gene, most notably in the genes for the proteins tau (MAPT) and progranulin (GRN)  On average, half of the children of someone with such a mutation will inherit the gene and develop FTD.
  17. 17.  The genetics of dementia with Lewy bodies (DLB) is not well understood,.  The symptoms of DLB overlap with those of both Alzheimer's disease and Parkinson's disease with dementia, and there is evidence that some of the risk genes for DLB are also known risk genes for these other dementias.  Whether these overlapping risk genes include APOE is not yet clear.
  18. 18.  People with Down's syndrome are at particular risk of developing dementia.  This is typically Alzheimer's disease, which can affect as many as 50 per cent of people with Down's syndrome who live into their 60s.  This increased risk because people with Down's have an extra copy of chromosome 21, and hence an extra copy of the amyloid precursor protein gene (APP) which is found on that chromosome which also linked to Alzheimer's disease.
  19. 19.  Huntington's disease is a rare progressive hereditary condition caused by a mutation in a particular gene (Huntingtin).  The course of the disease varies for each person, and dementia can occur at any stage.  Huntington's is inherited in a simple single- gene pattern.  Someone with Huntington's disease therefore has a 50 per cent chance of passing it to each child
  20. 20.  Indications:  Anyone who is worried about inheriting a form of dementia and who has a relative with the condition  If more than one family member affected by early onset Alzheimer's( particularly between the ages of 30 and 50)  For some families with early onset familial Alzheimer's disease it may be possible to identify a specific genetic mutation that is responsible for the disease in that family.  This sort of testing is called 'predictive testing', and is currently offered to people with genetic diseases with predictable inheritance patterns, such asHuntington's disease.
  21. 21.  Help genetic researchers understand the disease better and so lead to improved treatment  Encourage someone to adopt a healthier lifestyle  Help people to plan for the future.
  22. 22. However, genetic testing may create problems, for the following reasons:  A genetic defect cannot be repaired, .  A gene test might therefore raise anxiety without offering a clear course of action.  In the case of genetic testing for APOE variants there is a risk of reading too much into the test results.  Testing positive for one or two copies of APOE ε4 does not mean a person will definitely develop late onset Alzheimer's disease.  Testing negative for APOE ε4 does not guarantee that they will be free from Alzheimer's.  People testing positive for any genetic test could face discrimination affecting their ability to buy property, get insurance or plan financially for their old age.
  23. 23. It is anticipated that discoveries during the next few year will lead to the design of new mechanism-based on gene therapies that can be tested in animal models, and, eventually, these approaches will be introduced successfully into the clinic for the benefit of patients with this devastating illness.

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