Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: Potential genetic and phenotypic heterogeneity

Apolipoprotein E (APOE) is the only confirmed susceptibility gene for late- onset Alzheimer disease (AD). In a recent genomic screen of 54 families wit h late-onset AD, we detected significant evidence for a second late-onset A D locus located on chromosome 12 between D12S373 and D12S390. Linkage to th is region was strongest in 27 large families with at least one affected ind ividual without an APOE-4 allele, suggesting that APOE and the chromosome 1 2 locus might have independent effects. We have since genotyped several add itional markers across the region, to refine the linkage results. In analyz ing these additional data, we have addressed the issue of heterogeneity in the data set by weighting results by clinical and neuropathologic features, sibship size, and APOE genotype. When considering all possible affected si b pairs (ASPs) per nuclear family, we obtained a peak maximum LOD score bet ween D12S1057 and D12S1042. The magnitude and location of the maximum LOD s core changed when different weighting schemes were used to control for the number of ASPs contributed by each nuclear family. Using the affected-relat ive-pair method implemented in GENEHUNTER-PLUS, we obtained a maximum LOD s core between D12S398 and D12S1632, 25 cM from the original maximum LOD scor e. These results indicate that family size influences the location estimate for the chromosome 12 AD gene. The results of conditional linkage analysis by use of GENEHUNTER-PLUS indicated that evidence for linkage to chromosom e 12 was stronger in families with affected individuals lacking an APOE-4 a llele; much of this evidence came from families with affected individuals w ith neuropathologic diagnosis of dementia with Lewy bodies (DLB). Taken tog ether, these results indicate that the chromosome 12 locus acts independent ly of APOE to increase the risk of late-onset familial AD and that it may b e associated with the DLB variant of AD.