Alzheimer’s disease (AD) can be separated into 2 groups: Familial autosomal dominant AD (FAD) and late onset AD. Three genetic mutations are known to precipitate the development of FAD, and researchers are striving to identify other genes that may be involved in its development. The role of genetics with regard to late onset AD is less apparent. The APOE4 allele has been established as a risk factor for late onset AD, yet does not conclusively indicate future development of AD. Recent studies implicate a number of other genes that may play a role in late onset AD, and ongoing research appears promising in identifying such genes.
Familial Dominant AD (FAD)
FAD, an inherited form of AD with onset between 30 and 60 years of age, is a rare form of AD, accounting for only 5-10% of AD cases. Currently, it is known that certain genetic mutations on chromosome 1, 14, or 21 lead to the development of FAD. If one is found to carry any such mutation, he or she is basically certain to develop FAD. Researchers are currently investigating other genes that may play a role in the development of FAD as well.
Genetic Mutations Associated With FAD
Genetic mutations in critical regions of the amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2) genes typically result in increased levels of beta-amyloid protein, a component of the trademark plaques found in AD. Such mutations follow an autosomal dominant inheritance pattern, meaning that only one copy of the gene is necessary in order for offspring to develop FAD. Individual testing for such mutations is discussed below.
The discovery of these mutations established that genetics does indeed play a role in the development of AD and helped identify some of the components central to the development of AD. Furthermore, the discovery of a genetic link shed some light on why some people develop the rare form of early onset AD while the vast majority of cases occur after the age of 65. Further studies aim to identify other key players in the disease’s development.
Late Onset AD
Late onset AD, on the other hand, accounts for 90-95% of cases and usually occurs after the age of 65. While less is known about the role of genetics in the development of late onset AD, recent research implicates a number of genetic influences.
The Genetics of Late Onset AD
A genetic variation classified as a risk factor for the development of late onset AD is APOE4, an allele of APOE located on chromosome 19 that is found in approximately 25-30% of the general population. Most carriers of APOE4 do not go on to develop AD, and many individuals with AD are not carriers of APOE4. This differentiation from APP and presenilin mutations, which conclusively lead to early onset AD, must be made clear.
Recent studies have revealed 2 genes—sortilin-related receptor (SORL1) and GRB2-associated binding protein 2 (GAB2)—may be implicated in the development of late onset AD. Suppression of SORL1, a gene believed to traffic APP within cells, results in increased levels of beta-amyloid.(1) Mutations in the GAB2 gene appear to increase the risk of late onset AD in carriers of APOE4; suppression of the gene has been shown to form the building blocks of the protein tangles found in AD. Conversely, APOE4 carriers with a healthy GAB2 gene appeared to have a decreased risk of developing AD.(2)
Other studies have suggested that mutations in APP, known to be associated with FAD, may also play a role in the development of late onset AD.(3)
Genetic Testing for FAD and Late Onset AD
Predictive genetic testing for FAD is available only to those individuals whose family exhibit the specific inheritance pattern of FAD. Such testing is currently available for only one of the 3 known genes related to the disease, the PS1 gene. Testing for PS2 and APP mutations are available strictly for research purposes.
APOE4 testing is generally conducted only on individuals with suspected late onset AD or patients presenting with conditions that have been linked to the APOE gene, such as inherited high cholesterol and triglyceride levels or a skin condition known as xanthomatosis. However, individuals can now elect to undergo APOE4 testing by private companies such as Smart Genetics, which now offers such testing for as little as $399. Researchers and physicians are divided regarding the use of such tests. Many in the medical community are concerned about the emotional impact of this testing, as lay individuals may not fully understand the implications of testing positive for the defective gene (i.e., only a small percentage of carriers go on to develop the disease). Such private testing does not include any type of counseling, a component largely seen as crucial to this and other genetic testing. Growing concern regarding the impact on insurance coverage for individuals undergoing APOE4 testing is yet another matter of concern.
Currently, Canada does not perform clinical testing for the APOE4 variant in relation to the risk of developing late onset AD, as several international committees have recommended against such testing.
References
(1) Lee JH, Barral S, Reitz C: The Neuronal Sortilin-Related Receptor Gene SORL1 and Late-Onset Alzheimer’s Disease. Curr Neurol Neurosci Reports 2008, 8:384-391.
(2) Reiman EM, et al: GAB2 alleles modify Alzheimer’s risk in APOE epsilon4 carriers. Neuron 2007 Jun 7, 54(5):713-20.
(3) Pericak-Vance MA, et al: Am J Hum Genet 2008. Full reference not available. For more information regarding the study, go to http://www.med.miami.edu/news/view.asp?id=1045
