Please click on one of the subjects below for more more information about that subject. General Information Amyloid Precursor Protein Gene [APP] Preseneilin 1 and 2 Genes Apolipoprotein E Gene GENERAL INFORMATION     A variety of genes have been linked to alzheimer's disease including interleukin 6, alpha 2-macroglobulin, cathespin D, apolipoprotein E, presenilin 1, amyloid precursor protein, and others. Some genes have a major influence on the risk of contracting alzheimer's disease: such genes as presenilin 1 and amyloid precursor protein. Other genes,such as alpha 2-macroglobulin, are of less importance. Some alzheimer genes run in families,generation to generation. When alzheimer's disease runs in families like that, it is referred to as familial alzheimer's disease. About 5% of all alzheimer cases involve genes that run in families. The three genes involved in familial alzheimer's disease are: mutations in the amyloid precursor protein,mutations in presenilin 1,and mutations in presenilin 2. Familial alzheimer's disease strikes its victims as early as age 30,but usually between the ages of 40 and 60. When alzheimer's disease occurs before age 65, it is referred to as early-onset alzheimer's disease. Early-onset familial alzheimer's disease not only affects people at an earlier age, but it also is more virulent, and those affected by it suffer a swifter cognitive decline than those with late-onset alzheimer's disease. Late-onset alzheimer's disease, occurring after age 65, has a slower clinical downard progression. AMYLOID PRECURSOR PROTEIN GENE (APP)     Amyloid precursor protein, abbreviated as APP, is necessary for normal brain function. Research has shown that APP protects brain cells from injury and insult. Sometimes, however, for unknown reasons, APP is cleaved abonormally by enzymes, and a substance called amyloid beta peptide, is formed. Amyloid beta peptide, abbreviated as AB, is regarded as the key substance that causes alzheimer's disease. AB is directly toxic to brain cells, and even small quantities can irreversibly destroy brain cells.AB is especially prone to destroy a class of brain cells called cholinergic neurons, that use acetylcholine to transmit nerve messages. AB is produced from APP when either of two enzymes, called beta and gamma secretase, cleave APP abnormally, producing AB, which is 40 to 43 amino acids long. When everything works normally, an enzyme called alpha secretase cleaves APP so that amyloid beta is not produced. Please understand this concept,since virtually all alzheimer genes cause problems by elevating production of AB. One of these genes is the APP gene, located on Chromosome 21. Six different mutations have been identified in the APP gene. Usually,a mutation is dominant. This means that if you inherit one mutated gene, you have a high likelihood of contracting alzheimer's disease. If a mother or father has the mutated APP gene, the children each have a 50-50 chance of getting the disease. Mutations in the APP gene cause only a small amount of early-onset familial alzheimer's disease. Most early-onset alzheimer's disease is cause by mutations in the presenilin 1 and presenilin 2 genes. PRESENILIN 1 and 2 GENES     Presenilin 1 is a protein found in brain cells. Its function is unknown. However, it may be involved in protein production and trafficking, especially during early development. More than 40 different mutations have been found in the presenilin 1 gene, and these mutations associate with early-onset familial alzheimer's disease. The disease strikes as early as 28 and as late as 62, with an average age of onset in the mid-forties. Mutations in presenilin 1 tend to elevate levels of amyloid beta in the blood, cerebrospinal fluid, and brains of those affected by mutations. Again, mutations in the presenilin 1 gene are dominant. This means that if a mother or father has the mutated presenilin 1 gene that causes alzheimer's disease, then each of their children has a 50-50 chance of having the mutation. Those children with the mutation have an almost virtual certainty of developing the disease.     Presenilin 2 is a protein found in brain cells. Its function is unknown. Only a very small amount of early-onset familial alzheimer's disease is caused by mutations in the presenilin 2 gene. Only six different mutations have been isolated, in five German families and one Italian family. Presenilin 2 mutations are not dominant. That is, not every person affected by the mutation develops alzheimer's disease. The reason for this is not known. Genetic testing can identify who has a mutated APP, presenilin 1, or presenilin 2 gene. Most genetic counselors advise that genetic testing makes sense for families where mutations in APP or presenilin 1 abound, since the mutations tend to be dominant. Genetic counselors are not as certain about genetic testing for other alzheimer genes, such as apolipoprotein E4, since this gene is not dominant. That is, not everyone with an apolipoprotein E4 gene develops alzheimer's disease. Further, many persons with alzheimer's disease do not have an apolipoprotein E4 gene, which we will discuss next. APOLIPOPROTEIN E4 GENE     Apolipoprotein E is a protein found in the brain, cerebrospinal fluid, and bloodtream. Apolipoprotein E protects brain cells and is involved in cholesterol transport. Three genetic forms of apolipoprotein are known. These forms are called E2, E3, and E4. About 15% of the Caucasian population has an E4 gene. Persons who inherit an E4 gene from a mother or father have a more than 3-fold risk of developing alzheimer's disease late in life, after age 65. People who inherit an E4 gene from both mother and father, have ten times the normal risk of developing alzheimer's disease after age 65. It is not clear why or how E4 increases risk. The E4 allele is not dominant.This means that not everyone with an E4 allele develops alzheimer's disease. In fact, only about half of those positive for an E4 allele ever develop alzheimer's disease. Some other factor other than the E4 is needed to produce alzheimer's disease. For example, factors in the environment,may delay expression of the E4 gene. Genetic counselors do not advise being tested for the E4 allele, since is is not certain that everyone with the E4 allele develops alzheimer's disease.