Identifying peripheral drivers of Alzheimers disease using plasma proteomics

National Institute On Aging

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Abstract

The goal of this project is to use plasma proteomic methods to identify biological pathways outside the central nervous system that influence brain health and Alzheimer's disease. We are (1) determining which plasma proteins and protein networks are differentially expressed in individuals to go on to experience structural and functional brain changes, cognitive decline, and dementia, and (2) identifying causally relevant proteins and protein networks to prioritize for future mechanistic studies. This project leverages recent advancements in proteomic measurement that allow for the simultaneous quantification of thousands of unique proteins with high levels of reliability. This project has funded multiple iterations of protein measurement in the Baltimore Longitudinal Study of Aging (BLSA), a longitudinal cohort study started in 1958 in which participants have serial cognitive assessments, and more recently, serial brain magnetic resonance imaging (MRI) and positron emission tomography (PET) scans to measure amyloid-beta and tau. Using this rich set of cognitive and neuroimaging data, we are examining how specific proteins measured in plasma relate to cognitive decline and brain volume loss spanning multiple decades. This project takes two complementary approaches. We have so far applied the SomaScan platform (which measures the plasma level of 7,000 unique proteins) and performed the first technical assessment of the platform's reproducibility. More recently, we have used these protein measurements to identify the peripheral biological processes associated with cerebral small vessel disease and cognitive decline. We have ongoing efforts that are examining which circulating immune proteins (900+ unique proteins) promote and protect against progression in individuals with Alzheimer's disease. In addition, we are working with external cohorts, such as the Atherosclerosis Risk in Community (ARIC) Study and Whitehall II that employ the same proteomic platform to replicate and elaborate upon findings derived from the BLSA. By understanding the proteomic signature that precedes Alzheimer's disease and Alzheimers-related brain changes, we hope to better understand which biological pathways can be therapeutically targeted to reduce the burden of disease.