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Alzheimer's Disease
  Genes Can Cause Alzheimer's Disease

By Amy Adams, MS

Reviewed by Robin Bennett, MS, CGC
Last updated September 8, 2000

 

 

If you or someone in your family has Alzheimer's disease, relatives have a higher risk than the general population for developing the disease. In fact people with at least one first-degree relative (parent or sibling) with Alzheimer's disease are 3.5 times as likely to develop the disease. This risk increases for each additional relative with Alzheimer's disease. This strong tendency of Alzheimer's disease to run in families is due, in part, to mutations in certain genes. Scientists have found several genes that are involved in early onset Alzheimer's disease, but so far they do not know the gene responsible for inherited late-onset Alzheimer's disease. (For recent news about late onset Alzheimer's genes, see Related News below.)

 
 
 

Genetics of Early Onset Alzheimer's Disease

About five percent of all Alzheimer's disease is caused by a mutation in one of three genes.
About five percent of all Alzheimer's disease is caused by a mutation in one of three genes, called APP, presenilin 1 (PS1), and presenilin 2 (PS2). Each of these genes is inherited in a dominant fashion. This means that it is only necessary to inherit one mutated copy of the gene in order to develop Alzheimer's disease. Those who do inherit a mutated form of these genes tend to develop Alzheimer's disease early in life (younger than age 65) and have a strong family history of the disease.

The APP Gene

A mutation in the gene that makes APP is believed to be responsible for 5 to 20 percent of all early onset familial Alzheimer's disease.
In people with Alzheimer's disease, deposits called amyloid plaques build up in the brain. These are composed, in part, of a protein called beta-amyloid, which is a fragment of the amyloid precursor protein (APP). A mutation in the gene that makes APP is believed to be responsible for 5 to 20 percent of all early onset familial Alzheimer's disease. People with a mutation in the APP gene tend to develop Alzheimer's disease at around age 50.

So far, researchers have found six different mutations in the APP gene, the most common of which has been identified as the cause of Alzheimer's in 16 families of European and Japanese descent. Each of the other five mutations has only been found to cause Alzheimer's diseaes in a single family. Although each mutation is different, they all occur in the same region of the gene. This tells researchers that this gene region is important in order to make an APP that functions normally.

The PS1 Gene

Mutations in a gene called PS1 account for about half of all early onset Alzheimer's disease in families.
Mutations in a gene called PS1 account for about half of all early onset Alzheimer's disease in families. Despite its importance in the disease, researchers do not know what role PS1 normally plays in the body.

Researchers have found more than 40 different mutations in the PS1 gene that cause early onset Alzheimer's disease in families of different ethnic backgrounds.

People with mutations in PS1 develop Alzheimer's disease at the earliest age.
People with mutations in PS1 develop Alzheimer's disease at the earliest age, ranging from 29 to 62 but with an average age of 44 years. Families with a particular PS1 mutation tend to develop Alzheimer's at the same age.

In four families with mutations in PS1, those who develop Alzheimer's disease also have weakness in the legs and more extensive changes in their brains than most people with Alzheimer's disease.

The PS2 Gene

Mutations in PS2 have only been found in six different families.
The PS2 gene has a very similar sequence to the PS1 gene, and, like the PS1 gene, researchers do not know its normal role in the body. Mutations in the PS2 gene are very rare. In fact, mutations in this gene have only been found in six different families with Alzheimer's disease. One mutation accounts for Alzheimer's disease in five German families and the other is responsible for the disease in an Italian family.

Unlike the PS2 or APP genes, researchers have found people who have a mutation in the PS2 gene but did not develop Alzheimer's disease. This, and the longer duration of Alzheimer's disease in people with PS2 mutations, makes researchers think that mutations in PS2 cause a less aggressive form of Alzheimer's than in people with PS1 mutations. The age when people with PS2 mutation develop symptoms of Alzheimer's disease varies even in the same family, indicating that some environmental factors also influence when a person with a PS2 mutation develops the disease.

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Alzheimer's Susceptibility Genes

Not all people who inherit the E4 version of APOE will develop Alzheimer's disease, and not all people with Alzheimer's disease have this version of the gene.
People who inherit mutated APP, PS1, or PS2 genes are very likely to develop Alzheimer's disease at some point in their lives. These genes are considered predictive. However, other genes also exist that only influence a person's susceptibility to Alzheimer's disease, but do not mean that a person is more likely than not to develop the disease. The best studied of these is apolipoprotein E (APOE). APOE has functions throughout the body: transporting cholesterol, regulating the immune system, aiding in nerve regeneration, and metabolism.

There are four different forms of the APOE gene. Inheriting one of these forms — called E4 — increases a person's risk of developing Alzheimer's disease by three-fold. Inheriting two E4 copies of the gene increases risk by 12- to 15-fold. People with two copies of E4 also tend to develop Alzheimer's disease earlier in life than the general population. The E4 version of APOE is present in about 15 percent of all Caucasian people and is even more common in people of African descent. However, not all of these people develop Alzheimer's disease, and not all people who have Alzheimer's disease also have the E4 version of APOE. This means that other environmental or genetic factors are also required in order for a person to develop Alzheimer's. Genetic testing for the APOE gene is not recommended for healthy people. However, it may be a useful diagnostic test in someone with dementia.

what is alzheimers diseasetop what is alzheimers disease

Related News
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Certain memory problems early Alzheimer's sign
Alzheimer's disease mapped to chromosome 10
Gene increases risk of late-onset Alzheimer's
Researchers find evidence of a new Alzheimer's gene
Gene boosts football players' brain damage risk

References

Selkoe, D. J. (1996). Amyloid beta-protein and the genetics of Alzheimer's disease. J Biol Chem, 271, 18295-8.

Campion, D. et al. (1995). Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet, 4, 2373-7.

Sherrington, R. et al. (1996). Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant. Hum Mol Genet, 5, 985-8.

Corder, E. H. et al. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families [see comments]. Science, 261, 921-3.

Relkin, N. R. et al. (1996). The National Institute on Aging/Alzheimer's Association recommendations on the application of apolipoprotein E genotyping to Alzheimer's disease. Ann N Y Acad Sci, 802, 149-76.

Roses, A. D. (1996). Apolipoprotein E and Alzheimer's disease. A rapidly expanding field with medical and epidemiological consequences. Ann N Y Acad Sci, 802, 50-7.

 

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