About 25 percent of people who develop Alzheimer’s disease are related to other people with the disease. In these instances, researchers refer to the disease as familial because it seems to run in families. There are no known clinical or brain differences between people with familial Alzheimer’s and people who are the only ones in their families to get the disease, but people with familial Alzheimer’s do tend to have a different genetic makeup and an earlier age of disease onset than people with nonfamilial Alzheimer’s.
Early-Onset Familial Alzheimer’s Disease
Early-onset Alzheimer's disease refers to instances of Alzheimer’s that begin between the ages of thirty and sixty. This form of disease is rare, as fewer than 5 percent of all people who have Alzheimer's have the early-onset variety. Some cases of early-onset Alzheimer's have no known cause, but most of these cases (more than 61 percent, in fact) can be linked to particular genes and are familial. Indeed, most individuals with the familial form of Alzheimer’s also have an onset that is consistently before the age of sixty, often before the age of fifty-five.
Familial Alzheimer's disease is caused by any one of a number of different single-gene mutations on chromosomes 21, 14, and 1. Each of these mutations causes abnormal proteins to be formed. Mutations on chromosome 21 cause the formation of abnormal amyloid precursor protein; a mutation on chromosome 14 cause the formation of abnormal presenilin 1; and a mutation on chromosome 1 causes the formation of abnormal presenilin 2.
Scientists know that each of these mutations also plays a role in the breakdown of APP, a protein whose precise function is not yet known. This breakdown is part of a process that generates harmful forms of amyloid plaque, and these harmful plaques are a hallmark of Alzheimer’s disease. A child whose mother or father carries a genetic mutation for familial Alzheimer’s disease has a 50 percent chance of inheriting that mutation. If the mutation is in fact inherited, the child almost surely will develop familial Alzheimer’s disease.
The Dominantly Inherited Alzheimer Network (DIAN), an international partnership that is sponsored by the National Institute on Aging (NIA), is studying families who have a genetic mutation that causes early-onset Alzheimer's disease. By observing the biological changes that occur in these families long before symptoms appear, scientists hope to gain insight into how and why the disease develops in both its early- and late-onset forms. In addition, scientists are attempting to develop tests that will enable the diagnosis and treatment of Alzheimer's before the clinical signs and symptoms appear.
Late-Onset Familial Alzheimer’s Disease
Most cases of Alzheimer's are the late-onset form, which develops after age 60. The causes of late-onset Alzheimer's are not yet completely understood, but they likely include a combination of genetic, environmental, and lifestyle factors that influence a person's risk for developing the disease.
The single-gene mutations directly responsible for early-onset Alzheimer's disease do not seem to be involved in late-onset Alzheimer's, and researchers have not found a specific gene that causes the late-onset form of the disease. However, one 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, a gene that is found on chromosome 19 and that appears to contain the instructions for making a protein which helps carry cholesterol and other types of fat in the bloodstream. APOE comes in several different forms, or alleles, of which APOE ε2, APOE ε3, and APOE ε4 occur most frequently:
- APOE ε2 is relatively rare and may provide some protection against Alzheimer’s disease. If Alzheimer's occurs in a person with this allele, it generally develops later in life than it would for someone with the APOE ε4 gene.
- APOE ε3 is the most common allele, and it is believed to play a neutral role in the disease—neither decreasing nor increasing risk.
- APOE ε4 is present in about 25 to 30 percent of the population and in about 40 percent of all people with late-onset Alzheimer's. People who develop Alzheimer's are more likely to have an APOE ε4 allele than people who do not develop the disease.
Dozens of studies have confirmed that the APOE ε4 allele increases the risk of developing Alzheimer's, but how that happens is not yet understood. These studies also help explain some of the variation in the age at which Alzheimer's disease develops, as people who inherit one or two APOE ε4 alleles tend to develop the disease at an earlier age than those who do not have any APOE ε4 alleles.
APOE ε4 is called a risk-factor gene because it increases a person's risk of developing the disease. However, inheriting an APOE ε4 allele does not mean that a person will definitely develop Alzheimer's. Some people with one or two APOE ε4 alleles never get the disease, and others who develop Alzheimer's do not have any APOE ε4 alleles.
Using a relatively new approach called a genome-wide association study (GWAS), researchers have identified a number of genes in addition to APOE ε4 that may increase a person's risk for late-onset Alzheimer's, including BIN1, CLU, PICALM, and CR1. Finding these kinds of genetic risk factors helps scientists better understand how Alzheimer's disease develops and increases our likelihood of identifying possible treatments to study.
Although a blood test can identify which APOE alleles a person has, it cannot predict who will or will not develop Alzheimer's disease. It is unlikely that genetic testing will ever be able to predict the disease with 100 percent accuracy because too many other factors may influence its development and progression.
At present, APOE testing is used in research settings to identify study participants who may have an increased risk of developing Alzheimer's. This knowledge helps scientists look for early brain changes in participants and to compare the effectiveness of treatments for people with different APOE profiles. Most researchers believe that APOE testing is useful for studying Alzheimer's disease risk in large groups of people but not for determining any one person's specific risk.
In doctors' offices and other clinical settings, genetic testing is used for people with a family history of early-onset Alzheimer's disease. However, it is not generally recommended for people at risk for late-onset Alzheimer's.