This document summarizes the key genetic factors involved in Alzheimer's disease. It discusses the two main types of AD - early onset and late onset. For early onset AD, mutations on chromosomes 1, 14, and 21 can cause abnormal protein formation and amyloid plaque buildup. The APOE e4 gene is a major genetic risk factor for late onset AD. Testing for APOE alleles and other genetic risk factors can provide information for research but not definitively predict an individual's risk of developing AD. A thorough diagnostic evaluation includes medical tests, cognitive assessments, and input from family and friends.

1. By: Bethany Otwell, Joelle Petrei, Cayla Schaffer, and Jayde Wan
Wednesday Lab – Team 6
“Problem Table”

2.  AD is an irreversible, progressive brain disease characterized by the development of
amyloid plaques and neurofibrillary tangles, the loss of connections between nerve
cells in the brain, and the death of these nerve cells.
 AD has two types – early-onset and late-onset.
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3.  Alzheimer’s is considered to be a single-gene mutation disorder, however there are a
multitude of genes which can mutate to cause one of the many variants of the disease.
 Not all gene variants cause Alzheimer’s, but they increase the person’s genetic risk
factor or their chance of developing the disease.
 Early-Onset Alzheimer’s disease is inherited through a dominant autosomal method; if
one parent has the disease, there is a 50/50 chance their children will also have it.
 What the mutations do:
 Mutations to the chromosomes create increased amount of β-amyloid protein
which is a major component of the plaques formation in Alzheimer’s.
 Mutations also create abnormal amyloid precursor proteins (APP’s) which cause
plaque formation.
 Sometimes Early-Onset Alzheimer’s disease is referred to as a Familial Alzheimer’s
Disease (FAD), the difference is FAD refers to any type of Alzheimer’s (late or early
onset) which is passed through the generations.
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4.  In late-onset Alzheimer’s disease:
 Many studies link late-onset Alzheimer’s disease (Alzheimer’s occurring after the
age of 65) to the APOE gene, specifically the e4 region.
 Having the APOE e4 gene is not shown to be directly correlated to the disease,
however people with this gene have an increased risk of developing the disease
(APOE e4 is present in 25-30% of the population).
 Other genes such as SORL1, CLU, PICALM, and CR1 also have been identified
with increased risk of developing late-onset Alzheimer’s disease as well.
 In early-onset Alzheimer’s disease:
 5% of people with Alzheimer’s have early-onset Alzheimer’s (in the US alone,
that’s approximately 200,000+ people).
 There are three chromosomes which can have mutations that cause the disease:
 Chromosome 1 – leads to abnormal presenilin 2 formation.
 Chromosome 14 – leads to abnormal presenilin 1 formation.
 Chromosome 21 – leads to the formation of abnormal amyloid precursor
proteins (APP’s) which cause plaque formation.

5.  The most common mutation on chromosome 1 is located at STM2.
 This abnormality is fairly rare, but present in German descendants who
immigrated to an area near the Volga River in Russia during the 18th century.
 Though not as common as late-onset Alzheimer’s disease, this is a fairly common
mutation among those with early-onset Alzheimer’s.
 The discovery of this mutation led researchers to a better understanding of what causes
the toxic β-amyloid plaque buildup and has aided researchers in coming up with
solutions to slow or at least stop the disease in its tracks.
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6.  Mutations on chromosome 14 generally occur at S182.
 Mutation causes abnormal presenilin 1 which causes 80% of the inherited early-
onset Alzheimer’s disease.
 This mutation was identified in 1995 by a Canadian research team.
 Presenilin 1 clips larger proteins into β-amyloid and play a part in cellular apoptosis as
well as cellular death.
 Cells with presenilin 1 mutations are more vulnerable to cell death cause by stress
related incidents and maintaining healthy cellular connections.
 When tested in mice, cell death could be slowed or prevented by monitoring
calcium levels to prevent increases which could result in apoptosis.
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7.  The first gene mutation linked to Alzheimer’s disease was actually discovered on this
chromosome, the smallest chromosome in the human genome.
 Identified in 1991, the gene codes for APP which is an important protein in the
formation of the plaques found in Alzheimer’s patients.
 The APP mutant found on this gene is the rarest, accounting for only 2-3% or all
Alzheimer’s cases.
 Persons affected by Down Syndrome will also develop Alzheimer’s disease by the age
of 60; the chance of not developing the disease is slim to none.
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8.  Chromosomes 10 and 19 are associated with late-onset Alzheimer’s (chromosome 19
can carry the APOE gene mutation).
 Chromosome 12 can have a mutation at the alfa-2-macroglobulin (A2M) gene.
 When the gene is defective or mutated, studies have shown there may be higher
susceptibility to developing Alzheimer’s.
 The gene is important to break down and removing β-amyloid protein which
causes the plaques in Alzheimer’s patients.
 Having a chromosome 12 mutation may cause disruption in the function of the
synapses in the brain through formation of plaques which clog them or slow down the
nerve signals to prevent the release of important growth factors that keep cells healthy.
http://flagshipbio.com/wp-content/uploads/2010/01/Amyloid-Plaque-Brain-A2.jpghttp://www.pharmagazette.com/uploads/beta-Amyloid_plaques.gif

9.  The APOE gene is known as Apolipoprotein E, a gene responsible for making a
protein which combines lipids in the body to form lipoproteins.
 Lipoproteins are responsible for packaging cholesterol and other fats then
transporting them through the bloodstream.
 This lipoprotein in particular is known as a “very low-density lipoprotein”
(VLDL) which removes excess cholesterol from the blood to carry it to the liver
where it is processed; this prevents cholesterol buildup and lowers the chances of
heart attacks and strokes.
 The APOE gene variant creates excessive amounts of protein clumps, known as
amyloid plaques, which are found in the brains of affected people.
 Buildup of toxic amyloid β-peptide leads to neuron death which then goes on to create
the progressive signs and symptoms of the disorder, mainly memory loss.
http://data.gate2biotech.com/editor_images/Image/Eva/Beta_amyloid.jpg http://drugline.org/img/term/apolipoprotein-e-1153_1.gif

10.  Detailed patient history including:
 Description of how and when symptoms developed
 Description of person’s and family’s overall medical condition and history
 Assessment of person’s emotional state and environment
 Information from friends:
 Valuable insights from family or friends who notice personality and behavioral
changes; generally friends and family notice something is wrong before evidence
is able to be gained on tests.
 Medical testing:
 Blood tests and neurological functionality tests
 Question-and-Answer tests for memory, language skills, arithmetic ability, and
cognitive functions.
 Computed tomography (CT) scan or magnetic resonance imaging (MRI) test
which test for strokes, tumors, or reveal changes in brain structure due to AD.
 Neuroimaging: position emission tomography (PET) scans, single photon
emission computed tomography (SPECT), and MRI’s detect brain function or
structural changes.
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11.  Blood tests can be used to determine which APOE alleles a person has; this is not
indicative of whether or not a person will develop Alzheimer’s Disease.
 APOE tests are used in research participants with increased likelihoods of
developing AD to look for the most effective ways to prevent the symptoms from
showing or to at least slow them down from becoming debilitating.
 Though APOE tests may be helpful in population studies, small samples of the
population may find these tests useless as they do not state whether or not an
individual will develop the disease.
 Along with blood tests, genetic risk-factor tests can be performed to give an estimated
likelihood for the disease developing, however it is believed by some researchers it
may be impossible to create a test which predicts Alzheimer’s Disease (both early-
onset and late-onset) with 100% accuracy.
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12. https://www.youtube.com/watch?v=hKVcrPfmwU0

13.  Turkington, C. and Galvin, J.E. 2003. The Encyclopedia of Alzheimer’s Disease.
Facts on File, Inc., New York, 286 p.
 Sutton, A. L. 2011. Alzheimer’s Disease Sourcebook (5th Edition). Omnigraphics,
Inc., Detroit, 637 p.