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: o Genetic risk of Alzheimer Disease in African Americans is currently unknown. o 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: o Case-control and family-based studies of 5896 African Americans o Collected over a period of 30 years between 1989 and 2011 o Subject inclusion criteria required participants be 60 years or older o Diagnoses made according to NINCDS-ADRDA criteria

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

7. Results From: Variants in the ATP-Binding Cassette Transporter (ABCA7), Apolipoprotein E 4,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: o ABCA7 genotype o APOE genotype ABCA7 role o Functions in apolipoprotein-mediated phospholipid and cholesterol efflux from cells o affects transport of amyloid precursor protein through the cell membrane o involved in host defense through effects on phagocytosis by macrophages of apoptotic cells

9. Application Risk factors for Late-Onset Alzheimer Disease: o Dyslipidemia o Cardiovascular Disease o 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.