Disease Mechanisms: Interactions of peripheral systems and brain (Milestone 2.B)
Achieved
Timeline Start - End
2016 - 2021Research Implementation Area
Research on Disease MechanismsEstablish new research programs that employ data-driven, systems-based approaches to understand the interaction between peripheral systems (in particular: immune, metabolic, microbiome) and the brain and the impact of this interaction on brain aging and neurodegeneration. These efforts should integrate human and animal model research and characterize the extent to which molecular (epigenomic, transcriptomic and metabolomic) variation identified in peripheral tissues can be used as a proxy for inter-individual variation in the trajectories of brain aging, AD and AD-related dementias.
Success Criteria
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Launch at least 6 new research programs that use data-driven, systems-based approaches aimed at understanding the interaction between peripheral organ systems and the brain and the impact of this interaction on brain aging and neurodegeneration.
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Provide support for studies that align blood and brain omics from longitudinal mouse and other pre-clinical models with human blood and brain omics to enable cross-species dynamic modeling of the trajectory of brain aging and disease progression.
Summary of Key Accomplishments
NIA-funded research has identified a number of potential risk factors for AD related to peripheral organ systems, such as high blood pressure and changes in certain compounds produced as a result of metabolism. NIA has established seven research programs through seven targeted funding initiatives to better understand how these peripheral organ systems (e.g., cardiovascular, immune, metabolic, microbiome) influence normal and pathologic brain aging.
As one example, researchers have been exploring how the community of microbes in our digestive tract — known as the gut microbiome — affects our health. These gut microbes produce various compounds, such as fatty acids and bile acids, that can travel through the bloodstream and enter the brain. Studies have linked cognitive decline and AD to an increase in the level of certain bile acids from microbes.
Another of NIA’s initiatives, Molecular Mechanisms of the Vascular Etiology of Alzheimer’s Disease (M²OVE-AD), is generating a deeper understanding of the genes, proteins, and other compounds linking vascular and metabolic risk factors (e.g., diabetes, high cholesterol, high blood pressure) with AD.
One study funded via this initiative discovered that abnormal levels of liver enzymes were associated with AD and correlated with poor memory and thinking scores in those with the disease. Abnormal levels were linked to several changes in the brain: increased levels of amyloid, reduced glucose metabolism, and greater shrinkage in the parts of the brain involved in memory and thinking. This study adds to the growing body of evidence that metabolic disturbances play a role in AD processes.
The key accomplishments summary is current as of March 2022.
Accomplishments/Implementation Activities
Funding Initiatives
- RFA-AG-15-010 Interdisciplinary Research to Understand the Vascular Contributions to Alzheimer's Disease (R01)
- RFA-AG-15-018: Immune and Inflammatory Mechanisms in Alzheimer’s Disease (R01)
- PAR-17-029: Dynamic Interactions between Systemic or Non-Neuronal Systems and the Brain in Aging and in Alzheimer’s Disease (R01)
- RFA-AG-17-051: Exosomes: From Biogenesis and Secretion to the Early Pathogenesis of Alzheimer's Disease (R01)
- RFA-AG-18-027: Exosomes: From Biogenesis and Secretion to the Early Pathogenesis of Alzheimer's Disease (R01)
- RFA-AG-17-055: Brain Lymphatic System in Aging and Alzheimer's Disease (R01)
- PAR-18-596: Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01)
- NOT-AG-18-001 (#6): Deciphering the Glycosylation Code of Alzheimer’s Disease
- PAR-15-358: Capturing Complexity in the Molecular and Cellular Mechanisms Involved in the Etiology of Alzheimer’s Disease (R01)
- PAR-17-029: Dynamic Interactions between Systemic or Non-Neuronal Systems and the Brain in Aging and in Alzheimer’s Disease (R01)
- RFA-AG-20-013: Geroscience Approaches to Alzheimer's Disease (R01/R21) (Clinical Trial Not Allowed) (R01)
- RFA-AG-20-014: Geroscience Approaches to Alzheimer's Disease (R01/R21) (Clinical Trial Not Allowed) (R01)
- RFA-AG-17-055: Brain Lymphatic System in Aging and Alzheimer's Disease (R01)
- PAR-19-070: Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01)
- PAR-19-071: Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01)
- NOT-AG-19-012: Infectious Etiology of Alzheimer's Disease
- RFA-AG-21-002: Mechanisms of Rejuvenation and Age-Acceleration in Heterochronic Blood Exchange (R01)
- PA-18-738: Age-related Microbiota Changes and their Implications in Chronic Disease Prevention, Treatment and Progression (R01 Clinical Trial Optional)
- RFA-AG-21-002: Mechanisms of Rejuvenation and Age-Acceleration in Heterochronic Blood Exchange (R01 Clinical Trial Not Allowed)
- NOT-AG-21-041: Capturing Complexity in the Molecular and Cellular Mechanisms Involved in the Etiology of Alzheimer's Disease
- NOT-AG-21-042: Deciphering the Glycosylation Code of Alzheimer's Disease
- NOT-AG-21-043: Infectious Etiology of Alzheimer's Disease
- NOT-AG-21-053: Role of Age-Associated Metabolic Changes in Alzheimer's Disease
Research Programs and Resources
- Molecular Mechanisms of the Vascular Etiology of Alzheimer's Disease (M²OVE-AD) Consortium
- Dynamic Interactions between Systemic or Non-Neuronal Systems and the Brain in Aging and in Alzheimer’s Disease
- Alzheimer’s Gut Microbiome Project
- Brain Lymphatic System in Aging and Alzheimer's Disease (R01)
- 2018 NIH Alzheimer’s Research Summit: Session II and Session V
- Workshop: Infectious Etiology of Alzheimer's Disease
- Aging Research on COVID-19: A NIA Investigators’ Workshop
- Select projects funded in FY21
- Diabetes and brain amyloid in middle aged Hispanics
Research Highlights
- Workshop: Understanding the Role of the Microbiome in Aging and Age-Related Disorders