Complete genomic screen in late-onset familial Alzheimer disease: evidence for a new locus on chromosome 12

A gene on human chromosome 12 may be linked to late-onset Alzheimer's disease. Researchers used various genetic analyses to screen all chromosomes in 54 families with at least one member who had Alzheimer's disease. Fifteen chromosomes were identified as likely candidates and further analysis revealed that four of these chromosomes, namely 4, 6, 12, and 20, were the most likely candidates. Chromosome 12 in particular was most strongly linked to Alzheimer's disease, especially a region near the centromere. The centromere is a structure close to the midpoint of the chromosome.
Context.--Four genetic loci have been identified as contributing to Alzheimer disease (AD), including the amyloid precursor protein gene, the presenilin 1 gene, the presenilin 2 gene, and the apolipoprotein E gene, but do not account for all the genetic risk for AD. Objective.--To identify additional genetic risk factors for late-onset AD. Design.--A complete genomic screen was performed (N=280 markers). Critical values for chromosomal regional follow-up were a P value of .05 or less for affected relative pair analysis or sibpair analysis, a parametric loaf score of 1.0 or greater, or both. Regional follow-up included analysis of additional markers and a second data set. Setting.--Clinic populations in the continental United States. Patients.--From a series of multiplex families affected with late-onset ([is greater than or equal to] 60 years) AD ascertained during the last 14 years (National Insititute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association diagnostic criteria) and for which DNA has been obtained, a subset of 16 families (135 total family members, 52 of whom were patients with AD) was used for the genomic screen. A second subset of 38 families (216 total family members, 89 of whom were patients with AD) was used for the follow-up analysis. Main Outcome Measures.--Linkage analysis results generated using both genetic model-dependent (loaf score) and model-independent methods. Results.--Fifteen chromosomal regions warranted initial follow-up. Follow-up analyses revealed 4 regions of continued interest on chromosomes 4,6,12, and 20, with the strongest results observed for chromosome 12. Peak 2-point affecteds-only loaf scores (n=54) were 1.3, 1.6, 2.7, and 2.2 and affected relative pairs P values (n=54) were .04, .03, .14, and .04 for D12S373, D12S1057, D12S1042, and D12S390, respectively. Sibpair analysis (n=54) resulted in maximum loaf scores (MLSs) of 1.5,2.6,3.2, and 2.3 for these markers, with a peak multipoint MLS of 3.5. A priori stratification by APOEgenotype identified 27 families that had at least 1 member with AD whose genotype did not contain an APOE*4 allele. Analysis of these 27 families resulted in MLSs of 1.0,2.4,3.7, and 3.3 and a peak multipoint MLS of 3.9. Conclusions.--A complete genomic screen in families affected with late-onset AD identified 4 regions of interest after follow-up. Chromosome 12 gave the strongest and most consistent results with a peak multipoint MLS of 3.5, suggesting that this region contains a new susceptibility gene for AD. Additional analyses are necessary to identify the chromosome 12 susceptibility gene for AD and to follow up the regions of interest on chromosomes 4, 6, and 20. JAMA, 1997;278:1237-1241