R35AG072290

Illuminating the APOE Locus with Long-Read Sequencing and Targeted Genomics - Project Summary/Abstract

Alzheimer's disease (AD) is a common, progressive, and ultimately fatal brain disease. Currently approved treatments provide only minimal symptomatic benefits and do not stop the disease from progressing. The field is in dire need of novel drug targets which could lead to disease-modifying therapies.

The most common genetic risk factor for AD is the E4 variant of the apolipoprotein E gene (APOE4). The effect of APOE4 varies greatly between people of African ancestry and people of European ancestry.

The current study, Illuminating the APOE Locus with Long-Read Sequencing and Targeted Genomics, will apply a new genome sequencing technology (long-read sequencing) to the study of APOE and several other AD-relevant genes, including ABCA7.

Long-read sequencing will be performed on DNA from roughly 2000 African-Americans with AD and 2000 healthy older African-American control subjects, as well as DNA from roughly 5000 European-American AD patients and 5000 European-American controls. A subset of these patients will also have long-read sequencing of these genes' RNA derived from white blood cells, fibroblasts, or brain tissue.

These analyses will help us understand how local genetic variants near the APOE4 variant can alter the type or amount of the APOE4 protein and how this affects the risk of AD. Similar analyses will be done on ABCA7 and another 15-20 targeted genes that will be selected just before sequencing begins and following an up-to-date review of the AD genetics literature.

In addition to understanding the local variants regulating a gene and the protein it produces, long-read sequencing will be useful in detecting large, damaging genetic mutations that are easily missed with standard whole-genome sequencing.

The results will allow for more specific estimates of AD risk in individuals of diverse ancestral backgrounds and will provide novel targets for drug development.

The Leland Stanford Junior University

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]

California United States

State-Wide

Leadership Award for Alzheimer's Disease and Related Dementias Research (R35 Clinical Trial Not Allowed) (RFA-AG-21-007)

Amendment Since initial award the total obligations have increased 386% from $944,243 to $4,590,209.