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Genetic Variants Associated with Late-Onset Alzheimer Disease

Genetic Variants Associated with Late-Onset Alzheimer Disease. By: Sarah Hinton, University of Georgia 2014 Pharm.D. candidate Preceptor: Dr. Ali Rahimi. Alzheimer Disease. Most common type of Dementia

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Genetic Variants Associated with Late-Onset Alzheimer Disease

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  1. Genetic Variants Associated with Late-Onset Alzheimer Disease By: Sarah Hinton, University of Georgia 2014 Pharm.D. candidate Preceptor: Dr. Ali Rahimi

  2. Alzheimer Disease • Most common type of Dementia • Characterized as a degenerative disease that causes a gradual and irreversible loss of higher brain functions • Approximately 5.4 million Americans have Alzheimer Disease • Usually affects people > 65 years of age • Disease-attributable risk has been linked to the APOE E4 variant located on chromosome 19

  3. Study • "Variants in the ATP-binding Cassette Transporter (ABCA7), Apolipoprotein E e4, and the risk of Late-Onset Alzheimer Disease in African Americans" • Reitz, C., Jun, G., Naj, A., Rajbhandary, R., Vardarajan, B.N., Wang, L., Valladares, O., Lin, C., Larson, E.B., et. al. • JAMA 309.14 (2013): 1483-1992.

  4. Objective • Identify genetic loci associated with late-onset Alzheimer Disease in African Americans. • Rationale: • Genetic risk of Alzheimer Disease in African Americans is currently unknown. • Identification of disease-associated variants will provide targets for genetic testing, prevention, and treatment.

  5. Study Design • Alzheimer Disease Genetics Consortium assembled multiple data sets representing: • Case-control and family-based studies of 5896 African Americans • Collected over a period of 30 years between 1989 and 2011 • Subject inclusion criteria required participants be 60 years or older • Diagnoses made according to NINCDS-ADRDA criteria

  6. Methods • Genotyped and imputed single-nucleotide polymorphisms (SNPs) associated with Alzheimer Disease assessed in: • case-control data sets • family based data sets • Inverse variance-weighted meta analysis performed with the combined results from individual data sets: • with genome wide analyses • with gene-based tests for previously reported loci

  7. Results From: Variants in the ATP-Binding Cassette Transporter (ABCA7), Apolipoprotein E ϵ4,and the Risk of Late-Onset Alzheimer Disease in African Americans JAMA. 2013;309(14):1483-1492. doi:10.1001/jama.2013.2973

  8. Discussion • Late-Onset Alzheimer Disease in African Americans was significantly associated with variants in: • ABCA7 genotype • APOE genotype • ABCA7 role • Functions in apolipoprotein-mediated phospholipid and cholesterol efflux from cells • affects transport of amyloid precursor protein through the cell membrane • involved in host defense through effects on phagocytosis by macrophages of apoptotic cells

  9. Application • Risk factors for Late-Onset Alzheimer Disease: • Dyslipidemia • Cardiovascular Disease • Cerebrovascular Disease • Cardiovascular and Cerebrovascular Diseases are more prominent in African Americans. • Findings of current study suggest the role of lipid metabolism in Late-Onset Alzheimer Disease may have significant effects on disease management.

  10. References • Naj AC, Jun G, Beecham GW, et al. Common Variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet. 2011; 43(5):436-441. • Beecham GW, Martin ER, Li YJ, et al. Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am J Hum Genet. 2009; 84(1);35-43.g • Logue MW, Schu M, Vardarajan BN, et al; Multi-institutional Research on Alzheimer Genetic Epidemiology (MIRAGE) Study Group. A comprehensive genetic assiciation study of Alzheimer Disease in African Americans. Arch Neurol. 2011; 68(12):1569-1579. • Hancock DB, Levy JL, Gaddis NC et al. Assessment of genotype imputation performance using 1000 Genomes in African American studies. PLoS One. 2012; 7(11):e50610. • Chan SL, Kim WS, Kwok JB, et al. ATP-binding cassete transporter A7 regulates processing of amyloid precursor protein in vitro. J Neurochem. 2008;106(2);793-804. • Tanaka N, Abe-Dohmae S, Iwamoto N, Yokoyama S. Role of ATP-binding cassette transporter A7 in cholesterol homeostasis and host defense system. J Atheroscler Thromb. 2011;18(4):274-281.

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