My mother died of pneumonia at the age of 76 but she suffered from dementia during the last 10 years of her life. Doctors thought she had Alzheimer’s disease (AD) but since no autopsy was ever performed, the diagnosis was never confirmed. I come from a family with no history of cancer or heart disease. But there is this possibility of AD that hangs over my head. Last week, we addressed several questions about AD to Dr. Michael Rafii of the Memory Disorders Clinic at UCSD Perlman Ambulatory Care Center in La Jolla, California and of the University of California, San Diego. Today, I bring you the last part of this Q & A.
Today, Sept 21 is World Alzheimer’s Day.
QUESTION: There is a genetic component to Alzheimer’s. Yet, genetic markers for Alzheimer’s have yet to be identified. What makes Alzheimer’s so complex that it is extremely difficult to find genetic and biomarkers and treatment for the disease?
AD is most likely due to a combination of genetic susceptibility and environmental influence. 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.
Even if only one of these mutated genes is inherited from a parent, the person will almost always 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 the protein 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.
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.