Early-Onset Alzheimer’s

By: Bethany Otwell, Joelle Petrei, Cayla Schaffer, and Jayde WanWednesday Lab – Team 6

“Problem Table”

What is Alzheimer's? 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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Genetics Behind Alzheimer’s 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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Chromosomal Location 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.

Chromosome 1 - Mutations 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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Chromosome 14 - Mutations 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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Chromosome 21 - Mutations 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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Other Chromosomes 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.

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What is the APOE Gene? 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.

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Diagnostic Tools 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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Gene Testing for Alzheimer’s 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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Bill Holmstrom – Salem Firefighter

https://www.youtube.com/watch?v=hKVcrPfmwU0

Bibliography 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.