This competitive renewal grant application seeks to continue a collaboration that used genome-wide association data in large, prospective epidemiological cohorts, the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), with >2-6 decades of risk factor, dementia, AD, MRI and cognitive endophenotype data in >30,000 persons to identify new genes/loci underlying the risk of Alzheimer's disease (AD). It produced >50 publications, helped identify 9 novel loci for AD (BIN1 &EPHA1 first reached genome-wide significance in a CHARGE-lead publication), and 8 for AD endophenotypes. CHARGE helped found the International Genomics of Alzheimer Project (IGAP) and established collaborations with >25 cohorts/ consortia such as the Enhancing Neuro Imaging through Meta-Analysis (ENIGMA) consortium. However, genes identified to date collectively explain <35% of the observed AD heritability of 60-80%. The missing heritability could be partly explained by multiple low-frequency or rare genetic variants that can be detected cost-effectively via analysis of exome chip (EC) data now available in the original CHARGE and in 4 additional cohorts (the CHARGE-Plus sample: n=45,910, ~4058 with AD). In this application we propose the following:
Aim 1 : To use EC data to search for rare genetic variants related to incident clinical AD, and to AD endophenotypes. We have shown that GWAS of AD endophenotypes, e.g. hippocampal &total brain volumes, verbal memory can identify novel loci implicated in brain aging, and biological pathways underlying AD. We propose to use EC data to search for rare variants related to these established AD endophenotypes.
Aim 2 : To understand preclinical AD, the stage of early pathological changes 1-2 decades before clinical AD, during which AD is likely most amenable to intervention, we propose GWAS and EC analyses of emerging novel, sensitive MRI endophenotypes, cognitive and circulating biomarker (plasma ?-amyloid and clusterin) data in the entire CHARGE-Plus and in younger cohorts aged 30-65 years.
Aim 3 : To better understand the biology, epidemiological and public health significance of the identified genes we will study gene-gene interactions between known and novel loci, and gene-environment interactions both targeted (interaction of loci from Aims 1&2 with midlife cholesterol and BMI), and genome-wide. The CHARGE cohorts, with premorbid data on mid-life exposure to a wide-range of environmental covariates, are uniquely positioned to study such interactions and permit analyses of other covariates when indicated.
Aim 4 : Finally, we will explore the biology of the identified variants using bio-informatics annotation databases created in CHARGE, available systemic and brain mRNA, miRNA, methylation data (n~8000 &750, respectively), hippocampal neuronal expression in autopsy brains and in Drosophila tau &?-amyloid models. We seek modest analytic resources to leverage existing phenotypic and genotypic data worth millions, to discover new AD genes and potentially novel prevention and treatment approaches for AD.

Public Health Relevance

Alzheimer's disease (AD) is a major public health burden with no known prevention or treatment, but identifying new AD genes can uncover new biological pathways leading to novel treatments. We assembled an international collaboration of cohort studies and searched for common genetic variants causing AD leading to the identification of 9 novel genes for AD, 8 for MRI and cognitive function markers of AD;we propose to expand our studies to seek rare genetic variants for AD using exome chip data on 45,000 persons, 4000 with AD. We will also explore the genetics of preclinical AD in the 40,000 without clinical disease by studying newer, sensitive MRI markers and gene-environment interactions and study the expression in humans and function in Drosophila for the novel genes we find.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-PSE-P (02))
Program Officer
Miller, Marilyn
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Boston University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Li, Xinzhong; Wang, Haiyan; Long, Jintao et al. (2018) Systematic Analysis and Biomarker Study for Alzheimer's Disease. Sci Rep 8:17394
Chaudhury, Sultan; Patel, Tulsi; Barber, Imelda S et al. (2018) Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease. Neurobiol Aging 62:244.e1-244.e8
Zhou, Xiaopu; Chen, Yu; Mok, Kin Y et al. (2018) Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer's disease pathogenesis. Proc Natl Acad Sci U S A 115:1697-1706
Adams, Shayna; Conner, Sarah; Himali, Jayandra J et al. (2018) Vascular risk factor burden and new-onset depression in the community. Prev Med 111:348-350
Satizabal, Claudia L; Samieri, C├ęcilia; Davis-Plourde, Kendra L et al. (2018) APOE and the Association of Fatty Acids With the Risk of Stroke, Coronary Heart Disease, and Mortality. Stroke 49:2822-2829
Sondhi, Arjun; Rice, Kenneth Martin (2018) Fast permutation tests and related methods, for association between rare variants and binary outcomes. Ann Hum Genet 82:93-101
Guo, Caiwei; Jeong, Hyun-Hwan; Hsieh, Yi-Chen et al. (2018) Tau Activates Transposable Elements in Alzheimer's Disease. Cell Rep 23:2874-2880
Raghavan, Neha S; Brickman, Adam M; Andrews, Howard et al. (2018) Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. Ann Clin Transl Neurol 5:832-842
Jian, Xueqiu; Satizabal, Claudia L; Smith, Albert V et al. (2018) Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging. Stroke 49:1812-1819
Tynkkynen, Juho; Chouraki, Vincent; van der Lee, Sven J et al. (2018) Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer's disease: A prospective study in eight cohorts. Alzheimers Dement 14:723-733

Showing the most recent 10 out of 234 publications