Genetics of Alzheimer's disease

Less than 5% of AD is caused by dominant genes that are transmitted through families. In these families, people usually show symptoms well before the age of 65 and symptoms sometimes begin in the 30s. This form of AD is called early-onset familial Alzheimer's disease (EOFAD). Additionally, there are other genes that increase or decrease susceptibility to AD but do not cause the disease.

Three predisposition genes have been associated with EOFAD. They are presenilin 1 (PS1) on chromosome 14, presenilin 2 (PS2) on chromosome 1, and the amyloid precursor protein gene (APP) on chromosome 21. All of these genes affect the processing of the amyloid precursor protein and increase the generation of toxic beta-amyloid (Abeta 42), which creates the plaques in AD. All three of these genes are inherited as autosomal dominant genes, which means that carriers of the genes have a 50% risk of passing the gene to their offspring. Likewise, other first-degree relatives (parents and siblings) have a 50% chance of carrying the gene. Clinical testing is available for the PS1 gene, but because of the small number of families with mutations in PS2 and APP, testing for these genes is currently only done through research labs.

Up to 20% of presenile AD seems to be due to the presence of certain susceptibility genes that cause the disease to occur earlier in life than it would without the gene. Of these genes, the APOE gene has the clearest and strongest association. APOE is found in three different forms: APOE 2, APOE 3 or APOE 4. Like all other genes, each cell contains two copies (alleles) of the APOE gene. These alleles can be the same form or different forms of APOE. APOE 3 is the most common form of the gene and is found in approximately 75% of the population. APOE 4 has been associated with an increased risk for developing Alzheimer's. People with two copies of APOE 4 have a significant increased risk (16-fold) over the general population, and people with one copy have about a 3-fold increased risk. Unlike the predisposition genes, however, APOE is a susceptibility gene. Not everybody with APOE 4 develops AD. Similarly, people without APOE 4 can develop AD. Other genetic and environmental factors also influence susceptibility. Therefore, until preventative treatment is available, presymptomatic testing for APOE is not recommended.