R01AG082730

Genetic architecture of pure Alzheimer's disease and mixed pathology - co-occurring neuropathologies such as Lewy bodies, hippocampal sclerosis, and microinfarcts likely influence heterogeneity in genetic studies of Alzheimer's disease (AD).

The genetic architecture of these co-occurring neuropathologies is not clear. Most AD genetic analyses use clinical AD dementia phenotypes and are limited by phenotype misclassification: many clinical AD "controls" harbor AD pathology while clinical AD "cases" have no or minimal AD pathology.

Only 20% of pathology confirmed AD dementia cases have only AD pathology ("pure AD"); 80% have co-occurring neuropathologies ("mixed AD"). A complementary strategy is to perform genome-wide association studies (GWAS) specifically distinguishing between pure and mixed AD.

The overarching goal of this proposal is to further scientific understanding of pure AD and mixed AD by integrating neuropathology together with advanced statistical approaches and extensive multi-omics data.

Aim 1: Distinguish the genetic architecture of pure AD vs. mixed AD vs. pathology-free controls and determine how associations are driven by particular neuropathological patterns.

1A. Perform GWAS of pathology-confirmed AD controls vs. pure AD vs. mixed AD using a multinomial regression framework. We will also examine how associations are driven by particular neuropathological features furthering our understanding of underlying mechanisms.

1B. Infer possible mechanisms by integrating biological knowledge. We will perform transcriptome-wide analyses and gene-network analyses of pure AD and mixed AD, integrating human PPI data.

Aim 2: Identify factors specific to pure AD or mixed AD.

2A. Use machine learning and harmonized clinical data to isolate factors associated with pure or mixed AD. Identified clinical risk factors could be used for future clinical trial stratification.

2B. Perform genetic correlation analysis and Mendelian randomization to estimate correlated genetic effects and potential causal effects between candidate risk factor traits and pure or mixed AD. Genetic correlation analysis will gain novel insights into the shared genetic basis between biobank-scale GWAS traits and pure AD and mixed AD. We will follow-up significant correlations with local genetic correlation and Mendelian randomization (MR) to identify specific genomic regions contributing to the correlation and quantify causal effects of these traits on pure AD and mixed AD.

Aim 3. Characterize the cellular and molecular consequences of pure AD vs mixed AD. We will harness the data generated by the SEA-AD and the ROS-MAP studies to characterize the molecular changes occurring for our phenotypes at cell type resolution. We will perform abundance analyses (3A), differential gene expression (3B), and differential chromatin accessibility (3C) in each cell type across multiple brain regions. We will investigate loci from recent GWASs of AD dementia and candidates from Aim 1.

University Of Washington

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Seattle, Washington 981951016 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 208% from $973,770 to $3,003,566.