R01AG081768

Maeve: Microbiota mediated flavonoid metabolites for cognitive health - Abstract

Globally, populations are aging thereby increasing healthcare burden, overall cognitive impairment, and dementia including Alzheimer's disease (AD).

The lack of effective treatments makes it essential to develop new strategies for healthy cognitive aging, including interventions to slow or prevent cognitive decline.

A traditional Mediterranean diet, rich in polyphenols (PPs), may prevent or delay the onset of cognitive dysfunction in older adults, preserving healthy brain structure and function, and lowering the risk of AD.

These effects, mediated in part by gut microbiome-derived PP metabolites, highlight the role alterations in the brain-gut microbiome system play in neurodegeneration.

Moreover, high levels of circulating phenyl-Γ-valerolactones, neuroprotective compounds, exclusively produced by gut microbiota from flavan-3-ol-rich foods (e.g., cocoa, tea, berries) are associated with delaying the onset of cognitive dysfunction in older adults.

Intake of such PPs can also change gut microbial composition and function, altering the physiology of the host's secondary bile acid (BA) pool, affecting regulatory and signaling functions in the brain as well as cognitive decline and AD.

We hypothesize that, in older adults with enhanced AD risk, dietary intake of PPs maintains healthier brain features and cognitive function, and that this beneficial effect is mediated by gut microbiota metabolites of PPs and BAs.

In this multi-PI application by leaders in the field of brain-gut microbiome interactions, we will conduct a year-long, multi-center randomized double-blind placebo-controlled study in 300 older adults in the United States (validation sample of 100 from Northern Ireland) who are at enhanced risk of developing AD.

Coupled with this, behavioral interactions will be investigated with a murine fecal microbiome transplant model incorporating samples from high AD risk participants on a high PP supplement compared to a placebo.

We will apply multiple complementary approaches: meta and transcriptomic interrogation of the gut microbiome, targeted/untargeted metabolomics for microbiota-derived metabolites, multimodal brain imaging, assessment of cognitive function and inflammatory status, and advanced bioinformatic techniques for data integration.

The hypothesis is addressed as follows:

Aim A: Identify the protective effects of high intake of supplementary dietary PPs on brain and cognitive parameters in high AD-risk participants.

Aim B: Determine the effect of PP intake on the microbiome, inflammatory, and AD biomarkers in high AD risk participants.

Aim C: Explore causal relationships between PP intake and gut microbial metabolites, inflammatory and AD markers, brain parameters, and cognitive function.

Aim D: Utilize a reverse translational approach to identify changes in mouse brain and behavior by PP-induced alterations in the human gut microbiome.

Ultimately, we will establish the protective effects of regular dietary PP intake on cognitive function and on brain-gut microbiome interactions, ideally allowing the development of effective dietary regimes to prevent or delay the onset of AD in at-risk elderly, thereby reducing cognitive decline and healthcare costs.

Los Angeles University Of California

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]

Los Angeles, California 90095 United States

Single Zip Code

Early and Late Stage Clinical Trials for the Spectrum of Alzheimers Disease/Alzheimers Related Dementias and Age-Related Cognitive Decline (R01 Clinical Trial Optional) (PAR-23-081)

Amendment Since initial award the total obligations have increased 97% from $1,563,756 to $3,084,260.