The apolipoprotein E/CI/CII gene cluster and late-onset Alzheimer disease.
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 epsilon 4 and FAD in late-onset families; the epsilon 4 allele frequency was .51 in affected subjects, .37 in at-risk subjects, .11 in spouses, and .19 in unrelated controls. The differences between the epsilon 4 frequencies in affected subjects versus controls and in at-risk subjects versus controls were highly significant (standard normal deviate [ZSND]) = 7.37, P < 10(-9); and ZSND = 4.07, P < .00005, respectively). No association between the epsilon 4 allele and FAD was observed in the ENVG or VG groups. A statistically significant allelic association between epsilon 4 and AD was also observed in a group of unrelated subjects; the epsilon 4 frequency was .26 in affected subjects, versus .19 in controls (ZSND = 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[Zmax] = 0.61, recombination fraction [theta] = .30; model 2, Zmax = 0.47, theta = .20). For ApoE in late-onset kindreds, positive Z values were obtained when either allele frequencies from controls (model 1, Zmax = 2.02, theta = .15; model 2, Zmax = 3.42, theta = .05) or allele frequencies from the families (model 1, Zmax = 1.43, theta = .15; model 2, Zmax = 1.70, theta = .05) were used. When linkage disequilibrium was incorporated into the analysis, the Z values increased (model 1, Zmax = 3.17, theta = .23; model 3, Zmax = 1.85, theta = .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 (ZSND = 3.003, P = .003) and ApoCII (ZSND = 2.319, P = .016), when control allele frequencies were used but not when allele frequencies were derived from the families.
Yu
C E
CE
Division of Neurology, University of Washington, Seattle 98195.
Payami
H
H
Olson
J M
JM
Boehnke
M
M
Wijsman
E M
EM
Orr
H T
HT
Kukull
W A
WA
Goddard
K A
KA
Nemens
E
E
White
J A
JA
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D053302:Apolipoprotein C-I; D053304:Apolipoprotein C-II; D001056:Apolipoproteins C / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D005858:Germany / Q000208:ethnology; D006801:Humans; D016013:Likelihood Functions; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D010375:Pedigree; D011110:Polymorphism, Genetic; D012426:Russia
D053302:Apolipoprotein C-I; D053304:Apolipoprotein C-II; D001056:Apolipoproteins C; D001057:Apolipoproteins E