Two types of Alzheimer’s disease exist: familial AD (FAD), which follows a certain inheritance pattern, and sporadic AD, where no obvious inheritance pattern is seen. Because of differences in the age at onset, AD is further described as early-onset (occurring in people younger than 65) or late-onset (occurring in those 65 and older). Early-onset AD is rare (about 10 percent of cases) and generally affects people aged 30 to 60. Some forms of early-onset AD are inherited and run in families. Early-onset AD also often progresses faster than the more common, late-onset form.
All FAD known so far has an early onset, and as many as 50 percent of FAD cases are now known to be caused by defects in three genes located on three different chromosomes. These are mutations in the APP gene on chromosome 21; mutations in a gene on chromosome 14, called presenilin 1; and mutations in a gene on chromosome 1, called presenilin 2. Even if one of these three mutations is present in only one of the two genes inherited from the parent, the person will inevitably develop that form of early-onset AD. There is as yet no evidence, however, that any of these mutations play a major role in the more common, sporadic or non-familial form of late-onset AD. Scientists are now working to reveal the normal function of APP and presenilins and to determine how mutations of these genes cause the onset of FAD. Some evidence exists that the mutations in APP make it more likely that beta-amyloid will be snipped out of the APP precursor, thus causing either more total beta-amyloid or relatively more of the “sticky” form to be made. It appears that the presenilin mutations may contribute to the degeneration of neurons in at least two ways: by modifying beta-amyloid production or by triggering the death of cells more directly. Most people with early-onset AD and presenilin 1 and 2 mutations have more of the longer and “stickier” form of beta-amyloid in their brains than do those with the sporadic form. This suggests that mutations in the presenilins can in some way drive the production of this form of amyloid. Another theory about the possible roles for mutated presenilins in altering the production of beta-amyloid is that they interact directly with APP on the surface of neighboring cells, an interaction that eventually triggers beta-amyloid production. Other researchers suggest that mutated presenilins 1 and 2 may be involved in accelerating the pace of apoptosis, a name for one way in which cells are programmed to die.
Genetics play a role in the development of late-onset AD as well as FAD. In the early 1990s, researchers at the NIA-supported Alzheimer’s Disease Center at Duke University in Durham, North Carolina, found an increased risk for late-onset AD with inheritance of one or two copies of the apolipoprotein E epsilon4 (APOE e4) allele on chromosome 19 (Strittmatter et al., 1993). An allele is one of two or more possible versions of the same gene, each of which has a slightly different base sequence from the others (polymorphism). Different alleles produce variations in inherited characteristics, such as eye color or blood type. In this case, the variations are in the gene that directs the manufacture of the ApoE protein, which helps carry blood cholesterol throughout the body, among other functions. It is found in glial cells and neurons of healthy brains, but it is also associated in excess amounts with the plaques found in the brains of people with AD. AD researchers are particularly interested in three common alleles of the APOE gene: e2, e3, and e4. The finding that increased risk is linked with inheritance of the APOE e4 allele has helped explain some of the variations in age of onset of AD based on whether people have inherited zero, one, or two copies of the APOE e4 allele from their parents. The relatively rare APOE e2 allele may protect some people against the disease; it seems to be associated with a lower risk for AD and later age of onset if AD does develop. APOE e2 also appears to protect people with Down syndrome from developing AD-like damage. APOE e3 is the most common version found in the general population and may play a neutral role in AD.
The mere inheritance of one or two APOE e4 alleles does not predict AD with certainty; that is, unlike early-onset FAD, a person can have one or two APOE e4 alleles and not get the disease and a person who develops AD may not have any APOE e4 alleles. The ways in which the ApoE e4 protein increases the likelihood of developing AD are not known with certainty, but one possible theory is that it facilitates beta-amyloid buildup and this contributes to lowering the age of onset of AD.
Several new candidates for additional AD risk factor genes for late-onset disease have recently been identified, and this is an exciting avenue for new research. Building on the improving understanding of AD genetics, scientists can continue to look for clues as to which protein structures hasten the initiation of the disease process, what mechanisms cause AD, and what the sequence of events is. Once they understand these, they can then look for new ways to diagnose, treat, or even prevent AD.
One of the most intriguing issues in this area is possible differences in risk among various racial and ethnic groups. Some recent studies have shown that carrying an APOE e4 allele is a greater determinant of risk of AD in Caucasians than it is in Hispanic Americans or in African Americans. However, African Americans and Hispanic Americans may have a higher overall risk of AD than do Caucasians (Tang et al., 1998). Other studies have found conflicting results (Fillenbaum et al., 1998). Clearly, further investigation is needed to examine the role that ethnic and racial differences play in determining the risk of AD and the contribution of APOE and other genes to this risk. Current NIA-funded studies should provide some answers.
Chromosomes and Genes: Directing Every Aspect of Life
The nucleus of every human cell in a healthy person’s body contains a vast chemical information database that carries all the instructions the cell needs to carry on all its functions (the only exception is mature red blood cells, which have no nucleus). This database is DNA, which exists as two long, intertwined, thread-like strands–the double helix. These tightly coiled strands are packaged in units called chromosomes. Each cell has 46 chromosomes in 23 pairs. Usually people inherit one chromosome in each pair from each parent. Each chromosome is made up of linear arrays of four chemicals (bases) arranged in various sequence patterns. These sequence patterns are made up of many thousands of segments, called genes. In each gene, the bases are lined up in a different order, and these different sequences of bases direct the production of specific proteins. The proteins that are produced as a result of these genetic instructions determine the physical characteristics of living organisms and direct almost every aspect of the organism’s construction, operation, and repair.
Even one slight change in a gene’s DNA code can result in a faulty protein, and a faulty protein can lead to cell malfunction and possible disease. Changes in a gene’s DNA code are called mutations. Some mutations can cause disease. Mutations that do not directly cause disease and that occur relatively frequently are called polymorphisms. Everyone inherits a large number of these polymorphisms all along their DNA. Particular sets of polymorphisms vary in frequency among different ethnic groups. Some can affect protein structure, altering the efficiency with which metabolic reactions take place, but not so much as to cause disease on their own. When one of these alterations affects the likelihood that a person will develop a particular disease, it is called a genetic risk factor.
National Institutes of Health
National Institute on Aging
1999 PROGRESS REPORT ON ALZHEIMER’S DISEASE