Alzheimer's Disease and Genes

by National Institute on Aging

Scientists do not yet fully understand what causes Alzheimer's disease (AD). However, the more they learn about AD, the more they become aware of the important function genes play in the development of this devastating disease.

Genes

All living things are made up of basic units called cells, which are so tiny that you can only see them through the lens of a strong microscope. Most of the billions of cells in the human body have one nucleus that acts as a control center, housing our 23 pairs of chromosomes. A chromosome is a thread-like structure found in the cell's nucleus, which can carry hundreds, sometimes thousands, of genes. In humans, one of each pair of 23 chromosomes is inherited from each parent. The genetic material on these chromosomes is collectively referred to as the human genome. Scientists now believe that there are about 30,000 genes in the human genome. Genes direct almost every aspect of the construction, operation, and repair of all living things. For example, genes contain information that determines eye and hair color and other traits inherited from our parents. In addition, genes ensure that we have two hands and can use them to do things, like play the piano.

Genes alone are not all-powerful. Most genes can do little until spurred on by other substances. Although they are necessary in their own right, genes basically wait inside the cell's nucleus for other molecules to come along and read their messages. These messages provide the cell with instructions for building a specific protein.

Proteins are essential building blocks in all cells. Bones and teeth, muscles and blood, for example, are formed from different proteins. They help our bodies grow, work properly, and stay healthy. Amino acids are the building blocks of proteins. A gene provides the code, or blueprint, for the type and order of amino acids needed to build a specific protein. Sometimes a genetic mutation (or defect in a gene) can occur, leading to the production of a faulty protein. Faulty proteins can cause cell malfunction, disease, and death.

Scientists are studying genes to learn more about the proteins they make and what these proteins actually do in the body. They also hope to discover what illnesses are caused when proteins don't work right.

The Genetics of Alzheimer's Disease

Diseases such as cystic fibrosis, muscular dystrophy, and Huntington's disease are single-gene disorders. If a person inherits the gene that causes one of these disorders, he or she will usually get the disease. AD, on the other hand, is not caused by a single gene. More than one gene mutation can cause AD, and genes on multiple chromosomes are involved.

The two basic types of AD are familial and sporadic. Familial AD (FAD) is a rare form of AD, affecting less than 10 percent of AD patients. All FAD is early-onset, meaning the disease develops before age 65. It is caused by gene mutations on chromosomes 1, 14, and 21. Even if 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, all offspring in the same generation have a 50/50 chance of developing FAD if one of their parents had it.

Genes in Late-onset Disease

The majority of AD cases are late-onset, usually developing after age 65. Late-onset AD has no known cause and shows no obvious inheritance pattern. However, in some families, clusters of cases are seen. Although a specific gene has not been identified as the cause of late-onset AD, genetic factors do appear to play a role in the development of this form of AD. Only one risk factor gene has been identified so far.

Researchers have identified an increased risk of developing late-onset AD related to the apolipoprotein E gene found on chromosome 19. This gene codes for a protein that helps carry cholesterol in the bloodstream. The APOE gene comes in several different forms, or alleles, but three occur most frequently: APOE e2, APOE e3, and APOE e4.

People inherit one APOE allele from each parent. Having one or two copies of the e4 allele increases a person's risk of getting AD. That is, having the e4 allele is a risk factor for AD, but it does not mean that AD is certain. Some people with two copies of the e4 allele (the highest risk group) do not develop clinical signs of Alzheimer's disease, while others with no e4s do. The e3 allele is the most common form found in the general population and may play a neutral role in AD. The rarer e2 allele appears to be associated with a lower risk of AD. The exact degree of risk of AD for any given person cannot be determined based on APOE status. Therefore, the APOE e4 gene is called a risk factor gene for late-onset AD.

Scientists are looking for genetic risk factors for late-onset AD on other chromosomes as well. They think that additional risk factor genes may lie on regions of chromosomes 9, 10, and 12.

The National Institute on Aging (NIA) has launched a major study to discover remaining genetic risk factors for late-onset AD. Geneticists from the NIA's Alzheimer's Disease Centers are working to collect genetic samples from families affected by multiple cases of late-onset AD. Researchers are seeking large families with two or more living relatives with late-onset AD.

About the Author

www.nia.nih.gov
NIA, one of the 27 Institutes and Centers of NIH, leads a broad scientific effort to understand the nature of aging and to extend the healthy, active years of life. In 1974, Congress granted authority to form NIA to provide leadership in aging research, training, health information dissemination, and other programs relevant to aging and older people.