We found a very high prevalence of Alzheimer disease (AD) (20% of those 60 years or older) in an inbred Arab community in northern Israel. This observation is apparently unrelated to the APOE c4 allele which has a frequency of <4% in demented and non-demented elders. A low resolution genome scan and fine mapping studies uncovered AD susceptibility loci in several chromosomal regions that have been implicated in previous studies of outbred Caucasian populations. We also found association between AD and several single nucleotide polymorphisms (SNPs) in the angiotensin converting enzyme gene on chromosome 17. During our investigation of the genetic etiology of AD in this community, we discovered coincidentally a very high prevalence of hypertension which was associated with AD. Going forward, the primary focus of our project remains the genetic basis of AD. In light of emerging evidence for a vascular component to AD risk, we plan to expand the scope of the study to investigate genetic pathways for hypertension, and more specifically, the relationship between the two disorders in this population. To accomplish these goals, we will screen all persons residing in this community ages 65 and older (approximately 2,163) for dementia, and will obtain from a carefully selected subset of 750 cohort members (including 150 subjects meeting AD criteria, 150 subjects with essential hypertension, 150 subjects with both AD and hypertension, and 300 non demented, normotensivc controls) risk factor data and blood samples for biochemical and DNA studies and for establishing lymphoblastoid cell lines. Our scientific aims are: 1) Identify 100,000 base pair regions containing AD (and possibly hypertension) susceptibility genes on chromosomes 9, 10, 12 and 17 by profiling 600 SNPs spanning 15 million base pairs in each of the four previously implicated chromosomal regions using high throughput genotyping technology; and evaluate these data using allelic and haplotype association methods; 2) Fine-map disease loci in the 100 kb regions showing significant association in Aim 1 using a grid of SNPs in 20 kb intervals, and repeating this process iteratively with a higher density of SNPs until the maximum linkage disequilibrium is attained; 3) Evaluate association between disease and 50 genes within the intervals showing the strongest signals in Aim 2 by genotyping additional SNPs and sequencing as necessary; 4) Evaluate association between disease and 100 genes with an emphasis on genes previously implicated in AD and genes involved in vascular functioning; and 5) Determine the relative contributions of SNPs showing significant association to disease susceptibility and investigate interactions among SNPs from multiple loci and with other factors including plasma homocysteine levels and education. The ultimate goal of this study is to find new targets (genetic and non-genetic) for therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG017173-05
Application #
7111086
Study Section
Epidemiology of Clinical Disorders and Aging Study Section (ECDA)
Program Officer
Miller, Marilyn
Project Start
2000-09-30
Project End
2010-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
5
Fiscal Year
2006
Total Cost
$1,068,845
Indirect Cost
Name
Case Western Reserve University
Department
Neurology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Sims, Rebecca (see original citation for additional authors) (2017) Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet 49:1373-1384
Jun, Gyungah R; Chung, Jaeyoon; Mez, Jesse et al. (2017) Transethnic genome-wide scan identifies novel Alzheimer's disease loci. Alzheimers Dement 13:727-738
Jun, G; Ibrahim-Verbaas, C A; Vronskaya, M et al. (2016) A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry 21:108-17
Hohman, Timothy J; Cooke-Bailey, Jessica N; Reitz, Christiane et al. (2016) Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk. Alzheimers Dement 12:233-43
Karch, Celeste M; Ezerskiy, Lubov A; Bertelsen, Sarah et al. (2016) Alzheimer's Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci. PLoS One 11:e0148717
Mez, Jesse; Mukherjee, Shubhabrata; Thornton, Timothy et al. (2016) The executive prominent/memory prominent spectrum in Alzheimer's disease is highly heritable. Neurobiol Aging 41:115-121
Ridge, Perry G; Hoyt, Kaitlyn B; Boehme, Kevin et al. (2016) Assessment of the genetic variance of late-onset Alzheimer's disease. Neurobiol Aging 41:200.e13-200.e20
Hohman, Timothy J; Bush, William S; Jiang, Lan et al. (2016) Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium. Neurobiol Aging 38:141-150
Ghani, Mahdi; Reitz, Christiane; Cheng, Rong et al. (2015) Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals. JAMA Neurol 72:1313-23
Inzelberg, Rivka; Massarwa, Magda; Schechtman, Edna et al. (2015) Estimating the risk for conversion from mild cognitive impairment to Alzheimer's disease in an elderly Arab community. J Alzheimers Dis 45:865-71

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