Genetic Factors - Risk Factors For Alzheimers Disease: Alzheimers

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Genetic factors

When a family member has Alzheimer's, people often wonder about their own chances of developing the disease. While heredity is a major factor in a small number of families, for most people, genetics plays only a minor role or none at all.

Early-onset Alzheimer's disease

Genetics is most important in families with a history of early-onset Alzheimer's (occurring before age 50) stretching back for several generations. (The early-onset form accounts for less than 1% of all Alzheimer's cases.) Mutations in three genes are known to cause this type of Alzheimer's: amyloid precursor protein gene (APP), presenilin 1, and presenilin 2. All three genetic mutations increase the production of beta-amyloid, which is deposited in the plaques found in Alzheimer's disease. APP directs the production of amyloid precursor protein, a brain protein that, when fragmented, sometimes produces beta-amyloid.

If one parent has any of these mutations, each child has a 50% chance of inheriting the mutated form. A child who inherits the mutated gene will inevitably develop early-onset Alzheimer's disease.

The defective APP gene, found in some families with early-onset Alzheimer's, is located on chromosome 21. People with Down syndrome, a common cause of mental retardation, have an extra copy of this chromosome. This is notable because the similarities between Alzheimer's and Down syndrome are striking.

People with Down syndrome almost invariably develop Alzheimer's symptoms in middle age, if they live that long. Tiny amyloid deposits begin showing up in their brains during adolescence, some 20 years before the distinctive tangles and plaques appear. Whether the two disorders are genetically related is unclear, but at least one study found that Alzheimer's patients had a higher than expected number of relatives with Down syndrome.

Researchers hope that the discovery of the genetic mutations linked to Alzheimer's will shed new light on why the disease causes brain cells to die, and that this understanding will lead to the development of drugs that can protect these cells.

Late-onset Alzheimer's disease

One form (or allele) of a gene that directs the manufacture of a protein called apolipoprotein E (ApoE) has been linked to late-onset Alzheimer's. However, that gene doesn't explain all cases. The ApoE gene is located on chromosome 19 and comes in three alleles: E2, E3, and E4.

Everyone has two genes for ApoE, one inherited from each parent. It's possible to have any one of six combinations — either mixed alleles or a matched pair. The E3 allele is the most common; in fact, more than half the population has a double dose of E3. The relatively rare E2 may provide some protection against Alzheimer's disease. E4, the dangerous variant, is carried by 14% of the U.S. population and by as many as 46% of people with Alzheimer's who have a family history of the disease.

Having one E4 allele increases the risk of developing late-onset Alzheimer's (particularly in people ages 60–75) and lowers the age of onset. Having two E4 alleles strengthens these effects. It's not known exactly how the E4 allele works to increase the risk of developing Alzheimer's, but scientists believe it may play a role in the faulty clearing of beta-amyloid deposits from the brain. In theory, the accumulation of beta-amyloid in the brain sets in motion a series of events that leads to the destruction of nerve cells — but exactly why this abnormal protein is overproduced or not cleared efficiently remains a mystery. ApoE also shuttles cholesterol into and out of cells, and people with E4 are at increased risk of cardiovascular disease.

A pattern of family-based inheritance for late-onset Alzheimer's (age 60 or older) has been difficult to establish, so the chances of inheriting a defective gene are unknown. Having the E4 allele is no guarantee that you will develop the disease, and not having the allele is no guarantee that you won't. The E4 allele is a risk factor for — but not a cause of — late-onset Alzheimer's disease. This lead, while establishing that there is some genetic risk for late-onset Alzheimer's disease, provides no basis for testing the ApoE genotype in healthy individuals without dementia. Mutations on other genes believed to affect the risk of developing late-onset Alzheimer's are also being studied.

Last updated:	January 23, 2007