Context.— The only genetic locus universally accepted to be important as a risk
factor for late-onset Alzheimer disease (AD) is the apolipoprotein E (APOE) locus on chromosome 19. However, this locus does
not account for all the risk in late-onset disease, and a recent report has
suggested a second locus on chromosome 12p11-12.
Objective.— To look for evidence of linkage on chromosome 12 and to test for the
presence of the new locus in an independent sample of familial late-onset
Design.— Retrospective cohort study. As part of a 20-centimorgan genome screen
(approximately equal to 200 markers), we tested a series of 18 genetic markers
on chromosome 12 and carried out multipoint, nonparametric lod score and exclusion
Setting.— Clinic populations in the continental United States selected from the
National Institute of Mental Health AD Genetics Consortium.
Patients.— We selected samples for DNA analysis from affected sibling pairs, 497
subjects from 230 families with 2 or more affected individuals with probable
or definite AD with onset ages older than 60 years (mean±SD, 75±6
years). Within the families, we used the 2 probable or definitely affected
individuals. In families with more than 2 such cases available, we used all
of them; in families with only 2 such cases in which unaffected individuals
were available, we also sampled the oldest unaffected individual and used
genotype data from this unaffected individual to check for nonpaternity and
Main Outcome Measure.— Presence of linkage or locus on chromosome 12.
Results.— Although linkage analyses confirmed the presence of a genetic susceptibility
factor at the APOE locus in these families with late-onset
AD, we were unable to confirm the presence of a locus close to the marker D12S1042. A moderate lod score (1.91) was found near D12S98 close to the α2-macroglobulin locus
in the affected pairs in which both members did not possess an APOE ∊4 allele.
Conclusions.— APOE remains the only locus established to
be a risk factor for late-onset AD. We were unable to confirm that a locus
on chromosome 12p11-12 has a major effect on risk for late-onset AD, although
an effect smaller than that for APOE cannot be excluded.