Identification of multiple loci for Alzheimer disease in a consanguineous Israeli-Arab community

We have observed an unusually high prevalence of dementia of the Alzheimer type (DAT) in Wadi Ara, an inbred Arab community in northern Israel comprising similar to850 persons over the age of 60 years. Family studies revealed that more than one-third of the DAT cases are members of one hamula (tribal group) within Wadi Ara. To map chromosomal loci contributing to DAT susceptibility, we conducted a 10 cM scan in a series of five cases and five controls selected from this hamula. Markers from 18 chromosomal regions showed significant allelic association with DAT (P<0.05). Locations on chromosomes 2, 9 and 10 remained significant after testing additional affected and non-demented individuals. Significant associations were also observed for markers on chromosome 12 which overlap with a locus implicated in previous genome scans. Analysis of allele frequency distributions for 12 markers spanning 20 cM on chromosome 9 narrowed the possible location of an DAT susceptibility gene to a 13 cM interval between D9S157 and D9S259 (most significant result: P=2.3 x 10(-7)). Analysis of 14 markers spanning 24 cM on chromosome 12 narrowed the possible location to a 14 cM interval distal to the LRP1 locus (most significant result: P = 1.3 x 10(-6)). Evidence for linkage on chromosome 9 stemmed primarily from excess homozygosity of marker alleles in cases compared with controls, suggesting that the gene at this location behaves in either a recessive or additive fashion. The unique characteristics of this community together with the emergent human genome data should allow for the rapid identification of DAT genes in these candidate regions.