R01AG076019

Leveraging population-based human data to uncover mechanisms connecting Alzheimer's disease and common infections and facilitate vaccines repurposing for AD prevention - Accumulating evidence suggests that infections may play a major role in Alzheimer's disease (AD). However, the exact mechanism is unclear. Recent studies linked diverse microorganisms (viruses, bacteria, fungi) to AD-related traits. This indicates a possibility that the culprit may be not a specific microbe (or not only it) but a compromised host immunity that may increase brain vulnerability to various infections and related toxins.

Recent data (including our own) suggested that some vaccines may have broader than expected beneficial off-target effects on the immunity that span beyond the protection against specific disease and may reduce risks of seemingly unrelated disorders, including AD, as well as all-cause mortality. The broad objective of this project is to significantly improve our understanding of the connections between AD and infectious diseases and suggest new candidates for AD prevention based on repurposing of existing vaccines in older adults.

To address this objective, we will assess the impact of infectious diseases and vaccinations occurring at ages 65+ on AD-related traits in population-based human data, taking into account genetic and other factors. This study will employ advanced pseudo-randomization techniques ("proxy for clinical trials") that take into account multiple variables and bring the interpretation of study results closer to that seen in randomized clinical trials.

Specific aims:

Aim 1. Evaluate relationships between AD and common infectious diseases and vaccines in older adults. We will estimate and compare risks of AD and other dementias among older individuals diagnosed with herpes simplex, herpes zoster (shingles), bacterial pneumonia, flu, recurrent mycoses, and some other infections. We will also evaluate off-target effects of vaccinations against pneumonia, flu, and shingles on AD onset and survival to select promising candidate vaccines for repurposing for AD prevention.

Aim 2. Evaluate the impact of genes involved in AD and brain vulnerability to infections on associations of AD with infections and vaccines. We will select candidate genes from the literature that are involved in AD, BBB permeability, brain response to infection, and myelin repair, and test if such genes can influence associations between infections/vaccines and AD, or AD biomarkers, and may be used in personalized AD prevention, with repurposed vaccines matching particular genotypes.

Aim 3. Compare effects of infections and vaccines on AD vs. other major diseases and all-cause mortality. We will evaluate and compare associations of infectious diseases/vaccines with risks of AD and other diseases (cancer, CHD, stroke, diabetes), as well as all-cause mortality, to check for potential trade-offs. Such trade-offs are important to identify for optimizing AD prevention and avoiding the situation in which a protective factor for AD may have undesirable effects on other major diseases and/or survival.

Results of this project will significantly improve our understanding of infectious etiology of AD and connections between AD and common infectious diseases and will facilitate repurposing of existing vaccines for AD prevention in older adults.

Duke 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]

Durham, North Carolina 277054667 United States

Single Zip Code

Infectious Etiology of Alzheimer's Disease (R01 Clinical Trial Optional) (RFA-AG-21-034)

Amendment Since initial award the total obligations have increased 388% from $624,818 to $3,052,023.