The apolipoprotein E/CI/CII gene cluster and late-onset Alzheimer disease

Chang En Yu, Haydeh Payami, Jane M. Olson, Michael Boehnke, Ellen M. Wijsman, Harry T. Orr, Walter A. Kukull, Katrina A.B. Goddard, Ellen Nemens, June A. White, M. Elisa Alonso, Todd D. Taylor, Melvyn J. Ball, Jeffrey Kaye, John Morris, Helena Chui, Adele D. Sadovnick, George M. Martin, Eric B. Larson, Leonard L. HestonThomas D. Bird, Gerard D. Schellenberg

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92 Scopus citations


The chromosome 19 apolipoprotein E/CI/CII gene cluster was examined for evidence of linkage to a familial Alzheimer disease (FAD) locus. The family groups studied were Volga German (VG), early-onset non-VG (ENVG; mean age at onset <60 years), and late-onset families. A genetic association was observed between apolipoprotein E (ApoE) allele ε4 and FAD in late-onset families; the ε4 allele frequency was .51 in affected subjects, .37 in at-risk subjects, .11 in spouses, and .19 in unrelated controls. The differences between the ε4 frequencies in affected subjects versus controls and in at- risk subjects versus controls were highly significant (standard normal deviate [Z(SND)]) = 7.37, P < 10 -9; and Z(SND) = 4.07, P < .00005, respectively). No association between the ε4 allele and FAD was observed in the ENVG or VG groups. A statistically significant allelic association between ε4 and AD was also observed in a group of unrelated subjects; the ε4 frequency was .26 in affected subjects, versus .19 in controls (Z(SND) = 2.20, P < .03). Evidence of linkage of ApoE and ApoCII to FAD was examined by maximum-likelihood methods, using three models and assuming autosomal dominant inheritance: (1) age-dependent penetrance, (2) extremely low (1%) penetrance, and (3) age-dependent penetrance corrected for sporadic Alzheimer disease (AD). For ApoCII in late-onset families, results for close linkage were negative, and only small positive lod-score-statistic (Z) values were obtained (model 1, maximum Z [Z(max)] = 0.61, recombination fraction [θ] = .30; model 2, Z(max) = 0.47, θ = .20). For ApoE in late-onset kindreds, positive Z values were obtained when either allele frequencies from controls (model 1, Z(max) = 2.02, θ = .15; model 2, Z(max) = 3.42, θ = .05) or allele frequencies from the families (model 1, Z(max) = 1.43, θ = .15; model 2, Z(max) = 1.70, θ = .05) were used. When linkage disequilibrium was incorporated into the analysis, the Z values increased (model 1, Z(max) = 3.17, θ = .23; model 3, Z(max) = 1.85, θ = .20). For the ENVG group, results for ApoE and ApoCII were uniformly negative. Affected-pedigree- member analysis gave significant results for the late-onset kindreds, for ApoE (Z(SND) = 3.003, P = .003) and ApoCII (Z(SND) = 2.319, P = .016), when control allele frequencies were used but not when allele frequencies were derived from the families.

Original languageEnglish (US)
Pages (from-to)631-642
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number4
StatePublished - 1994

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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