There is relatively little known about the distribution of Alzheimer's disease (AD) around the world. Knowledge of high- or low-prevalence foci of disease may aid our understanding of disease mechanisms. Alzheimer's disease occurs less frequently in Asia than in Europe and North America, probably because of lower allele frequency of the apolipoprotein E (apo E) e4 allele. The disease appears to be also less common in India and Africa.
There are few studies of the disease in Arabs, and few in populations with a high level of consanguinity. We have found a remarkably high prevalence of the disease in Arabs residing in Israel.
In a study in Tunisia, unspecified dementia was found to be 3 times less prevalent than in the United States. Treves, Chandra, and Korczyn (1993) found a lower prevalence of presenile AD in Sephardi, as compared with Ashkenazi Jews, but more late-onset disease in Sephardi than Ashkenazi, perhaps because of lower levels of education in Sephardi. The state of Israel is comprised of about 5 million Jews and 1 million non-Jews, mostly Moslem Arabs. This Arab population of Israel is valuable for medical research because of a high level of inbreeding, large family size, high level of smoking exposure, high level of medical care available through the Israeli Health System, excellent demographic databases available from the government, absence of alcohol use because of the religious proscription, and high participation rate (>98%).
Consanguinity increases the prevalence in a population of autosomal recessive genes that may have undesirable characteristics. For example, an additional 1/16 of the variation of DNA is made homozygous by the inbreeding of a marriage of first-cousins. Conversely, the probability of
identifying recessive or quasirecessive susceptibility factors is enhanced by inbreeding. Childhood mortality is increased in offspring of first-cousin marriages by a factor of 1.4 to 1.7, and children born to consanguineous unions have poorer health than the offspring of nonconsanguineous unions (including malignancies, congenital abnormalities, mental retardation,
and physical handicap). Curiously, there are few studies of the effects of inbreeding on the health of adults. We have hypothesized that consanguinity in the Wadi Ara community has increased the prevalence of autosomal recessive genes that are responsible, in part, for the
increased prevalence of the disease.
It has been reported that 44% of all Arab marriages in Israel are consanguineous, with a mean inbreeding coefficient of .0192 (Jaber, Shohat, Rotter, & Shohat, 1997). The inbreeding rates for Israeli Arabs may be particularly high (as compared with Egyptians or Syrians) because mobility
was reduced for centuries by the Turks. At times in Arab communities, it has been required for children to marry into their own family in part to avoid sharing resources with competing family groups.
Linkage studies by the Boston University group and others focused on inbred Arab families have helped to locate genes for several inherited, neurological diseases, including Wilson's disease, spinal muscular atrophy, sensorineural deafness, and autosomal recessive Duchenne-like
muscular dystrophy. Of critical relevance, successes in mapping genes for Wilson's disease and deafness using inbred Arab kindreds facilitated the cloning of these genes, which were subsequently shown to have diseasecausing mutations prevalent in outbred populations from other parts of the world, including the United States.
All of the known Alzheimer-related genes (on chromosomes 21, 14, 1, and 19) are dominant (chromosomes 21,14,1) or codominant (chromosome 19). There are no known genes affecting the development of AD that are recessive, perhaps because there have been few studies of AD in populations with high levels of inbreeding. De Braekeleer et al. (1989) reported an association between inbreeding and the development of AD (inbreeding coefficient 9 times higher in AD cases than in controls) in a rural population in Quebec. Studies in the Old Order Amish have found a low prevalence of disease in this inbred community, also having a low frequency
of the apo E-e4 allele (.037). Inbreeding could be linked to AD through a confounding effect of education, but the association of inbreeding and education is controversial (found for a Saudi population but not for Israeli Arabs). We expect that there are recessive factors for AD Genetic and Environmental Risk Factors 15 because of indirect evidence: genetic modeling studies of AD in apo E-e4 negative families are unable to reject a recessive model (Rao et al., 1996).
However, it is difficult to evaluate recessive models in outbred populations. The high prevalence we have seen in our highly inbred Arab population in Israel might be due to the inculcation of recessive AD susceptibility alleles or to a dominant gene that became frequent by founder effect.
In a population-based study of AD, we have screened all elderly residents of Wadi Ara, an Arab community in northern Israel, and observed an unusually high prevalence (20.5% of those >60 years, 60.5% of those >85 years). This prevalence is higher than that found in other populations in Israel, China, Europe, or the United States, even after adjustment for
age, education, and gender, and is not due to increased frequency of the apo E-e4 allele (Corder, Saunders, Strittmatter, et al., 1993; Saunders, Strittmatter, Schmechel, et al., 1993) which is actually reduced in this community (0.035 for nondemented elders) as compared with other Caucasians.
DNA samples were collected randomly from 256 participants of the Wadi Ara study, aged 75 ± 9, 118 male, and their apo E genotype was determined by a PCR-based method (Chapman, Estupinan, Asherov, & Goldfarb, 1996). Of the 256 cases examined, 22 carried an apo E-e4 allele
(all heterozygous), including 3 of 34 with AD (apo E-e4 allele frequency 0.04), 8 of 128 nondemented elderly participants (apo E-e4 allele frequency 0.03), 7 of 56 with age-associated memory impairment (AAMI; apo E-e4 allele frequency 0.06), and 4 of 38 with other types of dementia and pseudodementia (apo E-e4 allele frequency 0.05). These data suggest that the
apo E-e4 allele is relatively uncommon in Arabs in Wadi Ara. In fact, this is the lowest frequency of apo E-e4 ever recorded. Although the possibility that it is associated with dementia was not excluded, it cannot explain the high AD prevalence in this population.
Pedigree studies showed that more than one of three of the 168 prevalent cases were from one hamula (extended family) of the 14 found in Wadi Ara. A lOcM genome scan showed significant association with a site that has been narrowed to 1.6 cM. Evidence for linkage stemmed primarily from excess homozygosity of one of the alleles for a marker in this region in the total sample of cases (15%) compared with controls (3%). The crude odds ratio of AD associated with this genotype was 5.7 (95% CI = 1.5,21.7).
The odds increased to 10.0 (1.3-75.9) after adjustment for age, sex, and systolic blood pressure. The observation of significant but different patterns of association within multiple hamulas suggests the existence of multiple recombination between the marker and the AD susceptibility locus. This genetic location notably overlaps a region showing evidence for linkage to AD in a genome scan (Kehoe et al., 1999). This location includes several genes, including a gene strongly related to lipid metabolism. We are currently working on the precise identification of the linked gene. We are also investigating the possibility that the high prevalence of AD in Wadi Ara is related to environmental risk factors and medical illness, including a high-fat diet, altered lipid metabolism, thyroid disease, smoking, hypertension, heart disease, and stroke.
