Disease Mechanisms: Interactions of peripheral systems and brain

Summary of Key Accomplishments

NIA-funded research has identified several 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 funded more than 90 projects through ten 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, the NIA-funded Centrally linked longitudinal peripheral biomarkers of Alzheimer’s in multi-ethnic populations (CLEAR-AD) program aims to discover new blood biomarkers, reflecting changes in the brain, of AD and its co-pathologies; and identify such signatures that detect and predict neuroimaging, fluid biomarker, and clinical changes across the Alzheimer’s spectrum. While this data-driven and systems-based program is ongoing, it has the potential to provide insight into the interactions between peripheral organ systems and the brain and the impact of this interaction on neurodegeneration.

Additionally, another NIA initiative (Molecular Mechanisms of the Vascular Etiology of Alzheimer’s Disease), 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.

A new initiative is exploring the role of the immune system in the aging brain and ADRD. Research funded through this initiative will examine the role of the adaptive immune system and innate immune system and their interaction at the brain borders in the etiology of AD/ADRD. Studies also will seek to understand the peripheral immune system in the onset and progression of neurodegeneration.

Further, recent studies have also shed light on the impact of peripheral organ systems on the brain. For example, one NIH-funded research team determined that certain types of lipids in the blood play a role in how the gene known as apolipoprotein E influences AD risk. In addition, NIH has established a consortium to bridge a gap in Alzheimer’s drug development by generating animal models that more closely mimic human characteristics of the disease.

Moreover, researchers have also been exploring how the community of microbes in our digestive tract — known as the gut microbiome — affects our health. For example, recent studies have linked cognitive decline and AD to an increase in the level of certain bile acids from microbes.

In addition, research has shown that immune cells known as microglia can help to remove amyloid plaques, which are associated with AD/ADRD, from the brain. These results suggest that treatments for Alzheimer’s disease that rely on the immune system to activate microglia, which can slow the progression of Alzheimer’s disease through the clearing of amyloid plaques, may be possible.

The key accomplishments summary is current as of September 2025.