The past project periods dissected the biologic heterogeneity of Alzheimer's disease (AD) and found that it is a chronic disease with a preclinical, mild, and dementia phase. We found that co-morbid pathologies contribute to the AD phenotype. We identified many genomic, medical, experiential, and psychological factors associated with cognitive decline and incident AD dementia. Finally, we investigated the neurobiologic pathways linking risk factors to clinical and pathologic AD phenotypes. Interestingly, only genomic variants were associated with cognitive decline and AD dementia, and with AD pathology. Recent GWAS studies have nominated many genomic variants for AD dementia. The overall goal of the proposed continuation is to identify brain proteins and proteoforms linking AD risk genes to AD endophenotypes, i.e., AD pathology and cognitive decline. The proposed study will build on results of recent GWAS by leveraging multi-layered genomic data and post-mortem biospecimens from two ongoing cohort studies of aging and dementia.
Aim 1 will sequence and do fine mapping of known AD risk genes to identify sequence variants and haplotypes associated with AD endophenotypes in a Discovery Cohort.
Aims two will conduct identical analyses in a Confirmatory Cohort and then conduct pooled analyses of both Cohorts to increase power.
Aim three will leverage available DNA methylation, H3K9 histone acetylation, miRNA, RNAseq, and public reference data to identify the molecular pathways linking genomic variants to transcripts and AD endophenotypes.
Aim 4 will use liquid chromatography mass spectrometry (LC-MS) proteomics techniques to measure protein and proteoform abundances, and to identify isoforms and post-translational modifications linking AD risk genes to AD endophenotypes. An exploratory aim will assess for pleitropy by exploring the relation of AD risk genes, transcripts, and proteins with other pathologic and clinical phenotypes, and AD risk factors. The proposed study represents the logical next step following the successful AD gene discovery efforts. It uses an innovative and timely approach to integrate genomic, epigenomic, and transcriptomic data from human brain, characterize the molecular events linking AD risk genes to AD endophenotypes. Then it identifies proteins, isoforms, and post-translational modifications linking AD risk genes with AD endophenotypes. These proteins and proteoforms will be high value therapeutic targets. The identification of these proteins will provide new directions for research and treatment and thereby have high and sustained impact in the field.

Public Health Relevance

Using an innovative and timely approach integrating genomic, epigenomic, and transcriptomic data from human brain, we will characterize the molecular events linking AD risk genes to AD phenotypes, and identify proteins, isoforms, and post-translational modifications linking AD risk genes to AD endophenotypes. The identification of these proteins will provide new directions for research and treatment and thereby have high and sustained impact in the field.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Multi-Year Funded Research Project Grant (RF1)
Project #
2RF1AG015819-16
Application #
8760760
Study Section
Neurological, Aging and Musculoskeletal Epidemiology Study Section (NAME)
Program Officer
Anderson, Dallas
Project Start
1998-09-30
Project End
2019-06-30
Budget Start
2014-09-30
Budget End
2019-06-30
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Rush University Medical Center
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
Ahmad, Faraz; Das, Debajyoti; Kommaddi, Reddy Peera et al. (2018) Isoform-specific hyperactivation of calpain-2 occurs presymptomatically at the synapse in Alzheimer's disease mice and correlates with memory deficits in human subjects. Sci Rep 8:13119
Jiao, Rong; Lin, Nan; Hu, Zixin et al. (2018) Bivariate Causal Discovery and Its Applications to Gene Expression and Imaging Data Analysis. Front Genet 9:347
Yang, Hyun-Sik; Yu, Lei; White, Charles C et al. (2018) Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ?4 haplotype status: a community-based cohort study. Lancet Neurol 17:773-781
Readhead, Ben; Haure-Mirande, Jean-Vianney; Funk, Cory C et al. (2018) Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus. Neuron 99:64-82.e7
Tasaki, Shinya; Gaiteri, Chris; Mostafavi, Sara et al. (2018) Multi-omic Directed Networks Describe Features of Gene Regulation in Aged Brains and Expand the Set of Genes Driving Cognitive Decline. Front Genet 9:294
Dawe, Robert J; Yu, Lei; Schneider, Julie A et al. (2018) Postmortem brain MRI is related to cognitive decline, independent of cerebral vessel disease in older adults. Neurobiol Aging 69:177-184
De Jager, Philip L; Ma, Yiyi; McCabe, Cristin et al. (2018) A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research. Sci Data 5:180142
Cheng, Hao; Xuan, Hongwen; Green, Christopher D et al. (2018) Repression of human and mouse brain inflammaging transcriptome by broad gene-body histone hyperacetylation. Proc Natl Acad Sci U S A 115:7611-7616
Gaiteri, Chris; Dawe, Robert; Mostafavi, Sara et al. (2018) Gene expression and DNA methylation are extensively coordinated with MRI-based brain microstructural characteristics. Brain Imaging Behav :
Power, Melinda C; Mormino, Elizabeth; Soldan, Anja et al. (2018) Combined neuropathological pathways account for age-related risk of dementia. Ann Neurol 84:10-22

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