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The APOE Gene Is an Alzheimer Disease Susceptibility Locus

المؤلف:  Cohn, R. D., Scherer, S. W., & Hamosh, A.

المصدر:  Thompson & Thompson Genetics and Genomics in Medicine

الجزء والصفحة:  9th E, P281-282

2026-01-17

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As presented in Chapter 9, the ε4 allele of the APOE gene is a major risk factor for the development of AD. The role for APOE as a major AD susceptibility locus was suggested by multiple lines of evidence, including linkage to AD in late-onset families, increased association of the ε4 allele with AD patients compared with controls, and the finding that apoE binds to the Aβ peptide. The APOE protein has three common forms encoded by corresponding APOE alleles (Table 1). The ε4 allele is significantly overrepresented in patients with AD (~40% vs ~15% in the general population) and is associated with an early onset of AD (for ε4/ε4 homozygotes, the age at onset of AD is ~10–15 years earlier than in the general population). Moreover, the relationship between the ε4 allele and the disease is dose dependent; two copies of ε4 are associated with an earlier age at onset (mean onset before 70 years) than with one copy (mean onset after 70 years). In contrast, the ε2 allele has a protective effect and correspondingly is more common in elderly subjects who are unaffected by AD (see Table 1).

Table1. Amino Acid Substitutions Underlying the Three Common Apolipoprotein E Polymorphisms

The mechanisms underlying these effects are not known, but apoE polymorphisms may influence the processing of βAPP and the density of amyloid plaques in AD brains. It is also important to note that the APOE ε4 allele is not only associated with an increased risk for AD; carriers of ε4 alleles can also have poorer neuro logic outcomes after head injury, stroke, and other neuronal insults. Although carriers of the APOE ε4 allele have a clearly increased risk for development of AD, there is currently no role for screening for the presence of this allele in healthy individuals; such testing has poor positive and negative predictive values and would therefore generate highly uncertain estimates of future risk for AD.