Researchers at Washington University School of Medicine in St. Louis have made a significant discovery by identifying proteomic changes linked to different forms of Alzheimer’s disease (AD).
This work is described in a paper titled “Proteomics of brain, CSF, and blood identifies molecular signatures for distinguishing sporadic and genetic Alzheimer’s disease,” published in Science Translational Medicine.
The study underlines the potential of proteomic analysis as a predictive model and biomarker for disease classification.
Different Forms of Alzheimer’s Disease
The research focused on three key categories: autosomal dominant AD related to specific gene variants, cases involving risk variants in the TREM2 gene, and sporadic AD, which is the most common form of AD. Sporadic AD, or “late-onset,” usually appears after age 65 and has no known genetic association.
Identifying Associated Proteins
The team used a multiplexed, single-stranded DNA aptamer assay to analyze 1,305 proteins across brain tissue, cerebrospinal fluid (CSF), and blood samples.
The study revealed significant associations between AD status and specific proteins in the brain, CSF, and blood.
In the brain, 12 proteins were significantly associated with AD status, and six of these were also found in both CSF and blood samples, exhibiting associations with AD status and age at onset.
These findings were validated using external datasets from various studies.
Proteomic Analysis in CSF and Blood Samples
In the CSF, 117 proteins were found to be significantly associated with clinical AD status. Of these, 27 proteins were also identified across brain tissue and blood samples.
External replication studies further validated the association of 40 proteins with AD status, highlighting the potential of CSF proteomics for identifying AD biomarkers.
The researchers also identified 26 proteins associated with sporadic AD status in blood plasma, with seven proteins replicated in brain and CSF samples.
Nine proteins were confirmed in association with AD through external replication studies.
Insights for Alzheimer’s Treatment
The study suggests that a combined proteomic analysis of brain tissue, CSF, and blood plasma can provide valuable markers to distinguish between sporadic and genetically defined AD.
Enrichment analyses highlighted pathways related to AD, Parkinson’s disease, and innate immune responses.
Interestingly, the programmed cell death and the intrinsic pathway for apoptosis, which includes several proteins, were found to be strongly enriched pathways for sporadic AD.
This indicates that some of the cell death associated with AD pathogenesis is regulated by apoptosis, the body’s normal process of eliminating damaged cells, rather than other types of cell death like necrosis or entosis.
The findings underscore the value of integrating proteomic analysis across various tissues and fluids to comprehensively understand AD biology and develop prediction models for individuals with specific genetic profiles.
This discovery offers promise for earlier diagnosis, personalized treatment strategies, and potentially improved patient outcomes in the future, although further validation is necessary.
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The study was published in Science Translational Medicine.
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