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AD Development and Genetic Factors
Early-onset AD
Nearly all cases of early onset AD (onset before age 65) which
comprises < 10% of AD cases, can be attributed to mutations
on chromosomes 1, 14, and 21. APP is coded on chromosome 21;
persons with Down's syndrome have 3 copies of this chromosome
(trisomy 21) and often develop amyloid plaques and AD at a relatively
young age.
Other known genetic findings in early-onset AD are a mutation in the APP gene on chromosome 21, mutations in presenilin 1 on chromosome 14, and mutations in presenilin 2 on chromosome 1. Both presenilin 1 & 2 are thought to code for membrane proteins that may be involved in processing APP. If one of the three mutations is present in one of the two genes inherited from a parent, the person will eventually develop early-onset AD.
Late onset AD About 10 years ago, researchers 3 discovered an increased risk for late-onset AD with inheritance of one or two copies of apolipoprotein e4 (APOE e4) allele on chromosome 19. APOE is a polymorphic liquid transport and repair protein found in the brain. Polymorphism refers to the fact that this gene has 3 allelic forms — APOE e 2, e 3, and e 4. APOE normally found in healthy neuronal tissue, but is observed in excessive concentrations in the neuritic plaques and also NFTs of AD. APOE e 2 may be protective against AD; it seems to be associated with a lower risk for AD and later age of onset if AD does develop. APOE e3 is the most common version found in the general population and may act neutrally in the development of AD. The presence of 2 APOE e 4 alleles is associated with an earlier onset of AD; it has been posited that each copy of APOE e 4 may lower age of onset by 7-9 years.5
The genotype of one or two APOE e 4 alleles does not predict the development of AD with 100% accuracy. An individual may be homozygous or heterozygous for APOE e 4 and not develop AD and individuals who develop AD may not carry any APOE e 4 alleles.
A public policy statement on the role and appropriateness of APOE testing was published in 1995 6 . The current recommendations support the use of APOE testing for diagnostic purposes only in conjunction with other testing during evaluations of patients with suspected AD. APOE testing is not recommended as a patient screening method. Clearly, further research is needed before this type of genetic testing becomes part of routine practice.