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One of the most important parts of unraveling the AD mystery is finding out what causes the disease. What makes the disease process begin in the first place? What makes it worse over time? Why does the number of people with the disease increase with age? Why does one person develop it and another remain healthy?

Some diseases, like measles or pneumonia, have clear-cut causes. They can be prevented with vaccines or cured with antibiotics. Others, such as diabetes or arthritis, develop when genetic, lifestyle, and environmental factors work together to cause a disease process to start. The importance of each one of these factors may be different for each individual.

AD fits into this second group of diseases. We don't yet fully understand what causes AD, but we know it develops because of a complex series of events that take place in the brain over a long period of time. Many studies are exploring the factors involved in the cause and development of AD.

Genetic Factors at Work in AD

In the last few years, painstaking detective work by scientists has paid off in discoveries of genetic links to the two main types of AD. One type is the more rare, early-onset Alzheimer's disease. It usually affects people aged 30 to 60. Some cases of early-onset disease are inherited and are called familial AD (FAD). The other is late-onset Alzheimer's disease. It is the most common form and occurs in those 65 and older

DNA, Chromosomes, and Genes: The Body's Amazing Control Center

The nucleus of almost every human cell contains a vast chemical information database. This database carries all the instructions the cell needs to do its job. This database is DNA. DNA exists as two long, intertwined, thread-like strands packaged in units called chromosomes. Each cell has 46 chromosomes in 23 pairs. Chromosomes are made up of four chemicals, or bases, arranged in various sequence patterns. People inherit material in each chromosome from each parent.

Each chromosome has many thousands of segments, called genes. The sequence of bases in a gene tells the cell how to make specific proteins. Proteins determine the physical characteristics of living organisms. They also direct almost every aspect of the organism's construction, operation, and repair. Even slight alterations in a gene can produce an abnormal protein, which, in turn, can lead to cell malfunction, and eventually, to disease. Any rare change in a gene's DNA that causes a disease is called a mutation. Other more common (or frequent) changes in a gene's DNA don't automatically cause disease, but they can increase the chances that a person will develop a particular disease. When this happens, the changed gene is called a genetic risk factor.

Genes and Early-onset Alzheimer's Disease

Over the past several decades, researchers working on AD realized that some cases, particularly of early-onset AD, ran in families. This led them to examine DNA samples from such families to see whether they had some genetic trait in common. Chromosomes 21, 14, and 1 became the focus of attention. The scientists found that some families have a mutation in selected genes on these chromosomes. On chromosome 21, the mutation causes an abnormal amyloid precursor protein (APP) to be produced. On chromosome 14, the mutation causes an abnormal protein called presenilin 1 to be produced. On chromosome 1, the mutation causes yet another abnormal protein to be produced. This protein, called presenilin 2, is very similar to presenilin 1. Even if only one of these genes inherited from a parent contains a mutation, the person will almost inevitably develop early-onset AD. This means that in these families, children have about a 50-50 chance of developing the disease if one of their parents has it.

Even though early-onset AD is very rare and mutations in these three genes do not play a role in the more common late-onset AD, these findings were crucial because they showed that genetics was indeed a factor in AD, and they helped to identify some key players in the AD disease process. Importantly, they showed that mutations in APP can cause AD, highlighting the key role of beta-amyloid in the disease. Many scientists believe that mutations in each of these genes cause an increased amount of the damaging beta-amyloid to be made in the brain.

The findings also laid the foundation for many other studies that have pushed back the boundaries of our knowledge and created new possibilities for future treatment. For example, in the last several years, a series of highly sophisticated experiments have shown that presenilin may actually be one of the enzymes (substances that cause or speed up a chemical reaction) that clips APP to form beta-amyloid (the protein fragment that is the main component of AD plaques). This discovery has helped clarify how presenilins might be involved in the early stages of AD. It has also given scientists crucial new targets for drug therapy and has spurred many new studies in the test tube, in animals, and even in people.

Tags: Alzheimer's Disease

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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.