A portion of the genetic component of Alzheimer disease (AD) is explained genes identified by positional cloning, targeted gene analysis and genome-wide association studies. With few notable exceptions, the functional variants in these genes and precise pathogenic mechanisms by which these variants lead to AD are unknown. We propose to direct our efforts to understanding AD genetic risk factors in African Americans (AAs), a group with a high incidence of dementia but with a different genetic architecture for AD than European Americans (EAs). Most notably, in AAs common variants in ABCA7 has an effect on AD risk comparable to that of APOE. Our recent discovery of two rare pathogenic AKAP9 mutations that are significantly enriched in AA AD cases, but absent in EAs altogether, suggests it is likely that there are population-specific AD-causing variants. We propose to use extensive clinical and genetic resources assembled by us and the AD Genetics Consortium to identify functional variants in AKAP9, ABCA7 and previously identified AD-associated genes that contribute directly to AD risk in AAs. To accomplish this goal we will resequence the coding and regulatory regions of these genes in 500 AA AD probands and 500 AA age-matched cognitively normal controls. Data will be evaluated using bioinformatic tools to identify functional variants that may directly influence AD pathogenesis. Potentially important functional variants will be tested for association in the discovery AA cohort and a replication AA cohort containing 1000 cases and 2000 controls. We will attempt to generalize these findings in EAs by evaluating top-ranked variants using publically available data to determine if variants identified in AAs are also important in EAs. Gene expression and RNA-Seq experiments will be performed in brain tissue from AA and EA cases and controls to identify variants that may regulate transcription of alternative isoforms. The most promising variants in ABCA7 and AKAP9 will be introduced into neuronal cells to evaluate their effects on expression and processing of APP, tau and other important AD markers. Finally, we will confirm the importance of these genes by demonstrating altered expression in neuropathologically confirmed brain specimens from AD cases and controls.

Public Health Relevance

The collective findings from this project will permit us to develop new hypotheses about pathogenic mechanisms leading to AD, identify proteins as targets for development of drugs to treat AD, and provide genetic markers for use in AD risk assessment and profiling subjects for clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG048927-04
Application #
9405828
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Miller, Marilyn
Project Start
2015-02-15
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
Chen, Ci-Di; Zeldich, Ella; Li, Yuexuan et al. (2018) Activation of the Anti-Aging and Cognition-Enhancing Gene Klotho by CRISPR-dCas9 Transcriptional Effector Complex. J Mol Neurosci 64:175-184
Ikezu, Tsuneya; Chen, Cidi; DeLeo, Annina M et al. (2018) Tau Phosphorylation is Impacted by Rare AKAP9 Mutations Associated with Alzheimer Disease in African Americans. J Neuroimmune Pharmacol 13:254-264
Cox, Jiayi Wu; Patel, Devanshi; Chung, Jaeyoon et al. (2018) An efficient analytic approach in genome-wide identification of methylation quantitative trait loci response to fenofibrate treatment. BMC Proc 12:44
Chung, Jaeyoon; Wang, Xulong; Maruyama, Toru et al. (2018) Genome-wide association study of Alzheimer's disease endophenotypes at prediagnosis stages. Alzheimers Dement 14:623-633
Bis, Joshua C; Jian, Xueqiu; Kunkle, Brian W et al. (2018) Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation. Mol Psychiatry :
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
Cukier, H N; Kunkle, B K; Hamilton, K L et al. (2017) Exome Sequencing of Extended Families with Alzheimer's Disease Identifies Novel Genes Implicated in Cell Immunity and Neuronal Function. J Alzheimers Dis Parkinsonism 7:
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
Mez, Jesse; Chung, Jaeyoon; Jun, Gyungah et al. (2017) Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans. Alzheimers Dement 13:119-129
Cukier, Holly N; Kunkle, Brian W; Vardarajan, Badri N et al. (2016) ABCA7 frameshift deletion associated with Alzheimer disease in African Americans. Neurol Genet 2:e79

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