Risk Factors for Alzheimer's Disease

Content provided by the Faculty of the Harvard Medical School
Excerpted from a Harvard Special Health Report

A number of factors have been linked to the risk of developing Alzheimer's disease. Some of these you can't control (such as age, gender, and family history); others you can influence (such as cholesterol levels, smoking, and weight).

Age and gender

Your age itself poses some risk. The risk usually rises after age 65 and continues to rise as you get older. Still, Alzheimer's is not an inevitable consequence of aging.

It also appears that women have a somewhat higher rate of Alzheimer's disease than men do. Women who live to at least age 55 have a one-in-six chance of developing Alzheimer's disease in their remaining lifetime. For men, the risk is one in 10. However, this effect is likely due to women's greater longevity.

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. Excessive amounts of the soluble form of APP are thought to be toxic to nerve cells.

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 (diagnosed at age 60 or older). 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 to 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.

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More than 5.3 million people in the United States are living with Alzheimer's disease, with a new person developing the disease every 70 seconds. Americans ages 65 and older with Alzheimer's and dementia pay three times as much in health care costs.