Vs. Rao et al., EVIDENCE FOR MAJOR GENE INHERITANCE OF ALZHEIMER-DISEASE IN FAMILIES OF PATIENTS WITH AND WITHOUT APOLIPOPROTEIN-E EPSILON-4, American journal of human genetics, 59(3), 1996, pp. 664-675
Apolipoprotein E (APOE) genotype is the single most important determin
ant to the common form of Alzheimer disease (AD) yet identified, Sever
al studies show that family history of AD is not entirely accounted fo
r by APOE genotype, Also, there is evidence for an interaction between
APOE genotype and gender, We carried out a complex segregation analys
is in 636 nuclear families of consecutively ascertained and rigorously
diagnosed probands in the Multi-Institutional Research in Alzheimer G
enetic Epidemiology study in order to derive models of disease transmi
ssion which account for the influences of APOE genotype of the proband
and gender, In the total group of families, models postulating sporad
ic occurrence, no major gene effect, random environmental transmission
, and Mendelian inheritance were rejected, Transmission of AD in famil
ies of probands with at least one epsilon 4 allele best fit a dominant
model, Moreover, single gene inheritance best explained clustering of
the disorder in families of probands lacking epsilon 4, but a more co
mplex genetic model or multiple genetic models may ultimately account
for risk in this group of families, Our results also suggest that susc
eptibility to AD differs between men and women regardless of the proba
nd's APOE status, Assuming a dominant model, AD appears to be complete
ly penetrant in women, whereas only 62%-65% of men with predisposing g
enotypes develop AD. However, parameter estimates from the arbitrary m
ajor gene model suggests that AD is expressed dominantly in women and
additively in men, These observations, taken together with epidemiolog
ic data, are consistent with the hypothesis of an interaction between
genes and other biological factors affecting disease susceptibility.