Download Alzheimer`s Disease: Genetics, Pathogenesis, Models, and






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
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
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

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 fulltime care.

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.
Both amyloid plaques and neurofibrillary tangles are clearly visible by
microscopy in brains of those affected 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 microtubuleassociated protein tau which has become hyperphosphorylated and
accumulate inside the cells themselves.


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)


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.

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




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.
APP and PS families of proteins

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; a
type 1 transmembrane glycoprotein; and Aph-1 and Pen-2, two
multipass transmembrane protein.






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.





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.

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 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.
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.




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, mostly 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.



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.



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.




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 singlegene pattern.
Someone
with
Huntington's
disease
therefore has a 50 per cent chance of
passing it to each child





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 as Huntington's
disease.



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.
However,
genetic
testing
may
problems, for the following reasons:






create
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.
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.
Few researchers think that the search for Alzheimer's genes
is over. But they also know genes aren’t the only cause of
the disease. More research will show how DNA, lifestyle
habits, and things in the environment play roles in making
people more likely to get the condition.