Scientists working in Oxford University and Duke University Medical Center this week reported the discovery of two new genetic risk factors for late-onset Alzheimer’s disease. Nearly 90 percent of all Alzheimer's cases are late-onset, and are thought to arise from the interaction of multiple genetic and nongenetic factors.

In 1993, the Duke group discovered the first susceptibility gene for late-onset Alzheimer’s, the E4 allele, or variant, of the apolipoprotein E gene on chromosome 19. People with this variant have a fourfold increased risk of developing the disease, but many people carrying the E4 allele do not develop the disease. The Oxford team, led by David Smith, has now found that a second gene on chromosome 3 greatly increases the risk for people who also carry the ApoE4 allele. The gene is for butyrylcholinesterase, an enzyme present in both amyloid plaques and neurofibrillary tangles. Their studies, which appear in this months Human Molecular Genetics, show that people age 65 and older who carry both the E4 allele and the K variant of the butyrylcholinesterase gene have a 30-fold increase in their risk of Alzheimer’s disease, compared with people who carry neither variant. About six percent of of the Caucasian population carry both variants, while over 50 percent carry neither.

In the second study, the Duke team that discovered the role of the ApoE4 allele reported that a new gene on chromosome 12 appears to be linked to between 10 and 15 percent of late-onset cases. The team found the linkage by studying families with a high incidence of late-onset Alzheimer’s disease. The finding is reported in this week’s Journal of the American Medical Association.—June Kinoshita

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Primary Papers

  1. . Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset confirmed Alzheimer's disease. Hum Mol Genet. 1997 Oct;6(11):1933-6. PubMed.