Identifying peripheral drivers of Alzheimers disease using plasma proteomics

National Institute On Aging

Investigators

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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 Alzheimers disease. First, we will determine 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. Second, we will identify 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 will fund 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 can examine how specific proteins measured in plasma relate to cognitive decline and brain volume loss spanning multiple decades. This project takes two complementary approaches. First, we will take a targeted approach to look at how baseline and longitudinal levels of a set of proteins previously implicated in Alzheimers disease (p-Tau181, soluble Trem2 sTREM2, and glial fibrillary acidic protein GFAP) relate to neurodegeneration and cognitive decline. We will also examine the longitudinal course of these proteins across the disease stage and identify potential peripheral drivers of each protein. Second, we will use the SomaScan platform to measure plasma level of 7,000 unique proteins in plasma collected concurrently with each BLSA participants 3T MRI scan. Using a proteome-wide approach, we will relate individual protein level to a number of neurocognitive outcomes, including symptomatic progression, cognitive decline, brain volume loss, and amyloid and tau aggregation. We will work with external cohorts, such as the Atherosclerosis Risk in Community (ARIC) Study, that employ the same proteomic platform to replicate and elaborate upon findings derived from the BLSA. We have recently completed measurements of the first set of plasma Alzheimers disease biomarkers in our study sample. Thus far, we have completed targeted protein measurement for baseline and longitudinal samples using the latest SomaLogic 7K platform. Initial analyses are currently underway. 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.