Alzheimer Disease in Wadi Ara

We are conducting genetic studies in an Arab community in northern Israel called Wadi Ara which has a very high rate of dementia. Wadi Ara (the Ara Valley) is comprised of three contiguous Arab villages (Ara-Ar’ara, Kafar-Qara and Umm-el-Fahm) located east of Hadera close to the border with the Palestinian Authority. The residents of Wadi Ara are mainly Palestinians, originally of Egyptian origin (1830-1840). Others have backgrounds from Southern Israel, Turkey, Syria and Lebanon. There are relatively few families in Wadi Ara, despite the size of the community. Residents of the area belong to one of about 14 hamulas, or tribal groups, and until recently there has been reportedly minimal immigration or emigration from the community since it was founded approximately 300-400 years ago. This geographic isolation, along with the relatively small number of founders has led to substantial consanguinity among its members. The area is primarily rural with agriculture as the primary occupation. The older population has very low rates of education and high rates of smoking. Meat consumption is high. Alcohol consumption is low because of religious beliefs. AD risk factors of special interest in Palestinian populations are heart disease, hypertension, and high fat diet.

We hypothesized that the increased prevalence of AD in this community is caused by one or more AD susceptibility alleles that are over-represented because of a founder effect and inbreeding. Our early low-resolution genome scan and subsequent fine-mapping identified AD susceptibility loci on chromosomes 2, 9, 10, and 12, all of which had been implicated in linkage studies in western European populations.1 Subsequently, we used a genome-wide set of ~300,000 SNPs to calculate measures of population stratification and inbreeding, and to identify regions of autozygosity. Although a high degree of relatedness was evident in both cases and controls, controls were significantly more related and contained more autozygous regions than cases (P=0.004).2 Eight autozygous regions on seven different chromosomes were more frequent in controls than cases, and 116 SNPs in these regions, primarily on chromosomes 2, 6, and 9, were nominally associated with AD.

We also posited that risk factors for vascular disease contribute additional risk in this population, and confirmed this idea with evidence for AD association with essential hypertension3 and single nucleotide polymorphisms (SNPs) in the angiotensin converting enzyme gene (DCP1).4 In that study, we identified significant evidence of association with a two-SNP haplotype composed of rs4343 (a synonymous coding SNP) and rs4351 (global P=7.5×10-7) in a sample containing 92 AD cases and 166 non-demented controls.  Individuals possessing the haplotype “GA” (frequency 0.21 in cases and 0.01 in controls) derived from these SNPs had a 45-fold increased risk of developing AD (95% CI 6.0–343.2) compared with those possessing any of the other three haplotypes.  The only other study to find significant results for this region was the recent GWAS conducted by the International Genomics Alzheimer Project (IGAP), which required 74,000 subjects to attain as strong an association of DCP1 with AD (P=3.1×10-7)5 as we established in our much smaller cohort.  Evidence from this cohort was also crucial to demonstrating association of AD with SORL1, thus establishing intracellular trafficking as a key pathway leading to AD.6 Subsequently, we confirmed association of AD in this cohort with several retromer genes which, like SORL1, are involved in recycling of amyloid-β.7

  1. Farrer LA, Bowirrat A, Friedland RP, Waraska K, Korczyn AD, Baldwin CT. Identification of multiple loci for Alzheimer disease in a consanguineous Israeli-Arab Community. Hum Mol Genet 2003; 12:415-422. PMID: 12566388
  2. Sherva R, Baldwin CT, Inzelberg R, Vardarajan B, Cupples LA, Lunetta K, Bowirrat A, Naj A, Pericak-Vance MA, Friedland RP, Farrer LA. Identification of novel candidate genes for Alzheimer disease by autozygosity mapping using genome wide SNP data. J Alz Dis. 2011; 23:349-359. PMID: 21098978
  3. Israeli-Korn SD, Masarwa M, Schechtman E, Abuful A, Strugatsky R, Avni S, Farrer LA, Friedland RP, Inzelberg R. Hypertension increases the probability of Alzheimer’s disease and of mild cognitive impairment in an Arab community in Northern Israel. Neuroepidemiology 2010; 34:99-105. PMID: 20016220
  4. Meng Y, Baldwin CT, Bowirrat A, Waraska K, Inzelberg R, Friedland RP, Farrer LA. Association of polymorphisms in the angiotensin-converting enzyme gene and Alzheimer disease in an Israeli-Arab community. Am J Hum Genet 2006; 78:871-877. PMID: 16642441
  5. Lambert J-C, Ibrahim-Verbaas CA,…170 co-authors… Farrer LA, M van Duijn CM, Van Broekhoven C, Moskvina V, Seshadri S, Williams J, Schellenberg GD, Amouyel P. Extended meta-analysis of 74,538 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 2013; 45:1452-1458. PMID: 24162737
  6. Rogaeva E, Meng Y, Lee JH, Gu Y-J, Zou F, Kawarai T, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, T.Cuenco K, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland R, Inzelberg R, Hampe W, Bujo H, Song Y, Andersen O, Graff-Radford N, Petersen R, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P. The sortilin-related receptor SORL1 is functionally and genetically associated with Alzheimer’s disease. Nat Genet 2007; 39:168-177. PMID: 17220890 
  7. Vardarajan BN, Bruesegem SY, Harbour ME, Inzelberg R, Friedland R, St. George-Hyslop P, Seaman MNJ, Farrer LA. Identification of Alzheimer disease associated variants in genes that regulate retromer function. Neurobiol Aging 2012; 33:2231.e15-2231.e30 PMID: 22673115