GENETIC-STUDIES ON CHROMOSOME-12 IN LATE-ONSET ALZHEIMER-DISEASE

Context. - The only genetic locus universally accepted to be important as a risk factor for late-onset Alzheimer disease (AD) is the apolipo protein E (APOE) locus on chromosome 19. However, this locus does not account for all the risk in late-onset disease, and a recent report ha s suggested a second locus on chromosome 12p11-12. Objective. - To loo k for evidence of linkage on chromosome 12 and to test for the presenc e of the new locus in an independent sample of familial late-onset AD cases. Design. - Retrospective cohort study. As part of a 20-centimorg an genome screen (approximately equal to 200 markers), we tested a ser ies of 18 genetic markers on chromosome 12 and carried out multipoint, nonparametric lod score and exclusion analyses. Setting. - Clinic pop ulations in the continental United States selected from the National I nstitute of Mental Health AD Genetics Consortium. Patients. - We selec ted samples for DNA analysis from affected sibling pairs, 497 subjects from 230 families with 2 or more affected individuals with probable o r definite AD with onset ages older than 60 years (mean +/- SD, 75 +/- 6 years). Within the families, we used the 2 probable or definitely a ffected individuals. In families with more than 2 such cases available , we used all of them; in families with only 2 such cases in which una ffected individuals were available, we also sampled the oldest unaffec ted individual and used genotype data from this unaffected individual to check for nonpaternity and genotyping errors. Main Outcome Measure. - Presence of linkage or locus on chromosome 12. Results. - Although linkage analyses confirmed the presence of a genetic susceptibility fa ctor at the APOE locus in these families with late-onset AD, we were u nable 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 alpha( 2)-macroglobulin locus in the affected pairs in which both members did not possess an APOE epsilon 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 eff ect on risk for late-onset AD, although an effect smaller than that fo r APOE cannot be excluded.