Using plasma proteomics to understand diseases of the brain: Alzheimer’s & cerebral small vessel disease

Abstract

Recent advances in high-throughput technology for the characterization of the human proteome have enabled the simultaneous assessment of thousands of circulating proteins at scale. Using this technology to examine plasma proteomic changes that precede the onset of dementia and Alzheimer’s disease may provide a window into the underlying disease biology and nominate new biomarkers and targets for intervention. By applying SomaLogic’s SomaScan® Assay to conduct a large-scale prospective analysis of the plasma proteome in cognitively normal individuals who later progress to dementia, we take a data-driven approach to discovery of early-stage blood-based biomarkers for Alzheimer’s disease, dementia, and cerebral small vessel disease. Through multi-cohort efforts which leverage network-based proteomics, genetics, brain imaging, and cerebral spinal fluid (CSF) biomarkers, we have identified a novel set of proteins, protein networks, and related biological pathways that may play a mechanistic role in age-related neurodegenerative conditions, including Alzheimer’s disease and vascular cognitive impairment.

Learning Objectives

This presentation will demonstrate how proteins measured in blood decades before dementia onset can be combined with genetic data to (1) identify novel early biomarkers for dementia, Alzheimer’s disease, and brain MRI characteristics indicative of cerebral small vessel disease, and (2) better understand the molecular pathways altered in the preclinical and prodromal phase of neurodegenerative disease. This presentation will also illustrate how SomaLogic’s SomaSignal® Tests can be used to enhance our understanding of how health characteristics and subclinical disease states influence brain aging and development of neurodegenerative disease.

• In middle-aged adults we identified proteins associated with dementia risk over a 25-year of follow-up period
• Proteins involved in proteostasis, immunity, synaptic function, and extracellular matrix organization were most strongly implicated in dementia risk
• Proteomics in combination with brain neuroimaging yielded insight about the biological processes underlying cerebral small vessel disease
• Incorporating genetic methods allowed us to nominate potentially causal proteins and genetically validate biomarkers
• SomaSignal Tests can be used to understand how health characteristics may influence Alzheimer’s disease and dementia risk

Keenan Walker, Ph.D.

Tenure-Track Investigator
Chief, Multimodal Imaging of Neurodegenerative Disease (MIND) Unit
Laboratory of Behavioral Neuroscience
National Institute on Aging, Intramural Research Program