We have found an unusually high prevalence of Alzheimer's disease (AD) in Wadi Ara, an inbred Arab community in northern Israel. Allele frequencies of 4.5% and 3.5% were found for the apolipoprotein E e4 allele among AD cases and nondemented controls, respectively, showing that other genetic or environmental influences must be responsible. Family studies revealed that more than one-third of the AD cases are members of one hamula (tribal group) within Wadi Ara. We hypothesize that the high risk of AD in this genetic isolate may be attributable to a founder effect enhanced by consanguinity. It is also possible that smoking or high fat diet are responsible. To map chromosomal loci contributing to AD susceptibility, we conducted a genome scan from specific hamulas and followed candidate regions found to be linked to disease. Markers from 18 chromosomal regions showed significant allelic association with AD. Smoking was very common in men but was not linked to the presence of AD in Wadi Ara, The unique characteristics of this community, together with the large amount of human genome data, should allow for the identification of AD genes in candidate regions.