Alzheimer's Disease

APP.

In 1991, a British research group identified mutations in the APP gene that occurred only in patients with AD in very rare families. (Less than twenty such families have been reported in the medical literature.) The mutations were not found in family members who did not have AD. The APP gene codes for amyloid precursor protein, one of whose degradation products is a main constituent of the senile plaques of AD.

PS1 and PS2.

In 1992, using linkage analysis of data from early-onset, autosomal-dominant families, researchers in Seattle, Washington; Jacksonville, Florida; and Antwerp, Belgium, almost simultaneously determined

that a then-unknown gene for early-onset AD was located on chromosome 14. In 1995, a research scientist in Toronto, Canada, identified this gene as PS1, which codes for the protein called presenilin1. Individuals who have mutations in the gene consistently develop AD. Also in 1995, using comparative genomic techniques, the Seattle research group cited above identified the PS2 gene, which codes for the protein termed presenilin 2. Using data from a few large, genetically isolated families with early-and late-onset disease, they determined that mutations in the gene consistently occur only in patients with AD.

APP, PS1, and PS2 are causative genes: When mutated, each causes AD. If a person has a mutated gene, he or she will develop the disease at about the same age as others who have the same mutation. The risk of developing the disease approaches 100 percent.

APOE.

In 1993 researchers in Durham, North Carolina, reported that one form (allele) of the APOE gene occurred more commonly in patients with late onset AD than was expected given its occurrence in the population as a whole. Numerous additional research groups corroborated the finding. The APOE gene occurs in three forms (alleles), determined by the DNA sequence. The three forms are termed APOEε2, APOEε3, and APOEε4, and they code for apolipoprotein E molecules differing from one another by only one or two amino acids. APOE is a susceptibility gene; it imparts an increased risk of disease occurrence but by itself does not cause the disease. The presence of the ε4 form (APOEε4) in either one or two copies in an individual increases the likelihood that the individual will develop AD. Occurrence may depend on other genetic factors or environmental factors or some combination from each category.

Additional families exist with early-onset, autosomal-dominant AD with no APP, PS1, or PS2 mutations. Such families provide evidence that there may be additional causative genes. Whole-genome-scan analyses reported in the late 1990s provide evidence of additional susceptibility genes on chromosomes 9, 10, and 12. The genes located on these chromosomes have yet to be identified.