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Disease Mechanisms: Interactions of peripheral systems and brain (Milestone 2.B)


Timeline Start - End

2016 - 2021

Research Implementation Area

Research on Disease Mechanisms

Establish 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

  • 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.

  • 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. 

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