Friday, September 4, 2009

Confirmed Genetic Causes of Alzheimer's Disease

Alzheimer disease has a genetic cause in up to 80 percent of cases, according to a study of nearly 12,000 twin pairs from the Swedish Twin Registry at Karolinska Institutet.

Alzheimer's and Genetics

Perhaps the most investigated field of the new millennium is genetics. Diseases such as cystic fibrosis, muscular dystrophy, and Huntington's disease are single-gene disorders. If a person inherits the gene that causes one of these disorders, he or she will usually develop the disease.

Researchers have observed that having a parent or sibling with Alzheimer’s disease does increase one’s risk somewhat above the general population’s risk of developing the disease, but such a family history should not cause undue anxiety. Nonetheless, some people with such family histories, and some without such histories, wish to have a genetic test that will answer the question: Will I be next?

Alzheimer's disease, however, is not caused by a single gene, which makes the genetic link to the disease much more complication.

The Genetics of Alzheimer’s Disease

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. Both types have genetic links.

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Early-Onset AD

Early-onset AD is a rare form of AD, affecting only about 5 percent of all people who have AD. It develops in people ages 30 to 60.

Some cases of early-onset AD, called familial AD (FAD), are inherited. FAD is caused by a number of different gene mutations on chromosomes 21, 14, and 1, and each of these mutations causes abnormal proteins to be formed. Mutations on chromosome 21 cause the formation of abnormal amyloid precursor protein (APP). A mutation on chromosome 14 causes abnormal presenilin 1 to be made, and a mutation on chromosome 1 leads to abnormal presenilin 2.

The chromosome 21 gene also intrigues Alzheimer's researchers because of its role in Down syndrome. People with Down syndrome have an extra copy of chromosome 21 and, as they grow older, usually develop abnormalities in the brain like those found in Alzheimer's disease.

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, 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 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.

In general, even if only one of these mutated genes is inherited from a parent, there is a significant chance for person to develop early-onset AD. This inheritance pattern is referred to as “autosomal dominant” inheritance. In other words, offspring in the same generation have a 50/50 chance of developing FAD if one of their parents had it.

Scientists know that each of these mutations causes an increased amount of the beta-amyloid protein to be formed. Beta-amyloid, a major component of AD plaques, is formed from APP.

These early-onset findings were critical because they showed that genetics were involved in AD, and they helped identify key players in the AD process. The studies also helped explain some of the variation in the age at which AD develops.

Late-Onset AD

Most cases of Alzheimer’s are of the late-onset form, developing after age 60. Scientists studying the genetics of AD have found that the mutations seen in early-onset AD are not involved in this form of the disease.

Although a specific gene has not been identified as the cause of late-onset AD, one predisposing genetic risk factor does appear to increase a person’s risk of developing the disease. This increased risk is related to the apolipoprotein E (APOE) gene found on chromosome 19. APOE contains the instructions needed to make a protein that helps carry cholesterol in the bloodstream. APOE comes in several 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 AD does occur in a person with this allele, it develops later in life than it would in someone with the APOE ε4 gene.
  • APOE ε3 is the most common allele. Researchers think it plays a neutral role in AD—neither decreasing nor increasing risk.
  • APOE ε4 occurs in about 40 percent of all people who develop late-onset AD and is present in about 25 to 30 percent of the population. People with AD are more likely to have an APOE ε4 allele than people who do not develop AD. However, many people with AD do not have an APOE ε4 allele.
Dozens of studies have confirmed that the APOE ε4 allele increases the risk of developing AD, but how that happens is not yet understood. These studies also have helped explain some of the variation in the age at which AD develops, as people who inherit one or two APOE ε4 alleles tend to develop AD at an earlier age than those who do not have any. APOE ε4 is called a risk-factor gene because it increases a person’s risk of developing AD. However, inheriting an APOE ε4 allele does not mean that a person will definitely develop AD. Some people with one or two APOE ε4 alleles never get the disease, and others who develop AD do not have any APOE ε4 alleles.

Scientists believe that four to seven other AD risk-factor genes exist and are using a new approach called a genome-wide association study (GWAS) to help speed the discovery process. Another possible risk-factor gene, SORL1, was discovered in 2007. This gene is involved in transporting APP within cells, and its association with AD has been identified and confirmed in three separate studies. Researchers found that when SORL1 is present at low levels or in a variant form, beta-amyloid levels increase and may harm neurons.

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Update 04-27-12:

The existence of two forms of Alzheimer's—early- and late-onset—has long baffled scientists. Of the estimated five million Americans who suffer from Alzheimer's, only a few thousand are diagnosed with an early-onset form of the affliction, which affects people before the age of 65. This rare early-onset form is thought to be hereditary and scientists have associated multiple genetic mutations contributing to its occurrence. Late-onset Alzheimer's, although more common, has been the bigger mystery. One variant of the APOE gene-—sometimes known as the Alzheimer's gene—is linked to the late-onset disease. But the APOE gene, unlike dominant early-onset genes, does not determine whether a person will ultimately have dementia.

Now there's evidence that late-onset Alzheimer's has a genetic basis similar to that of early-onset Alzheimer's. By sequencing select genes associated with the latter, along with frontotemporal dementia, researchers at Washington University in Saint Louis and other institutions found that patients with late-onset Alzheimer's carry some of the same genetic mutations as those with the early-onset form. The evidence, released February 2012, bolsters the argument that the forms of Alzheimer's that appear at different life stages should be classified as the same disease. As to why the disease appears earlier in some cases, the scientists speculated that those patients diagnosed relatively early in life carry more genetic risk factors for the disease.

This study's use of rapid genetic sequencing, the authors noted, may provide a model for more precise identification of dementias. Within the study, the researchers identified patients who may have been misdiagnosed as having Alzheimer's; the genes of these patients suggested that they had another type of dementia. Given the heritable component, patients with a family history could be screened to detect and diagnose Alzheimer's early.

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