Alzheimer Disease 13


For a general phenotypic description and a discussion of genetic heterogeneity of Alzheimer disease, see 104300.


Liu et al. (2007) conducted a genome screen of 103 patients with late-onset AD who were ascertained as part of the Genetic Research in Isolated Populations (GRIP) program that was conducted in an isolated population from the southwestern area of the Netherlands. Genealogic information resulted in an extremely large and complex pedigree of 4,645 members. The pedigree was split into 35 subpedigrees to reduce the computational burden of linkage analysis. The strongest evidence for linkage, hlod = 5.20 at marker D1S498, was obtained at chromosome 1q21 (AD13). Approximately 30 cM upstream of this locus, at 1q25 (AD14; 611154), another peak was found (hlod = 4.0 at marker D1S218). Liu et al. (2007) noted that these 2 loci were in a linkage region spanning 1q21-q31 identified by Zubenko et al. (1998), Hiltunen et al. (2001), Myers et al. (2002), and Blacker et al. (2003). Haplotype analysis showed that the 2 linkage peaks on chromosome 1q21 and 1q25 are explained by different haplotypes, of 15 cM and 21 cM, respectively, segregating in different families. The 1q21 region was not replicated when testing for association with cognitive function as an endophenotype of AD in 197 distantly related subjects. Liu et al. (2007) concluded that although they could not exclude the possibility of a false positive finding, given the strength of the linkage signal and previous evidence it was more likely that there is a rare mutation in a major gene in this region that could not be identified by association analysis in a small sample.