Did you know that many conditions that originate outside of the brain can influence dementia risk?
At our recent FOG Live: Next Gen Proteomics event, Keenan Walker (Investigator & Chief of the Mind Unit, National Institute on Aging (NIA/NIH)) explains why this is the case, Here, we summarise the key takeaways from his talk.
How does the proteome influence dementia and Alzheimer’s risk?
According to Keenan’s talk, systemic health conditions and cellular aging processes outside the central nervous system can influence the proteome. This leads to abnormal protein expression across various tissue types, and these proteins then get into the circulation.
Specifically, Keenan highlighted that conditions like diabetes, hypertension and cardiometabolic/inflammatory disorders can confer greater risk for dementia. The hypothesis is that proteins released into the bloodstream from these systemic disease processes may mediate the relationship between these peripheral conditions and brain health/dementia risk.
However, many of the proteins in question have not yet been identified.
Finding biomarkers
Keenan and his team used a large-scale proteomics approach to identify novel proteins associated with dementia risk that had not been previously discovered.
They utilised high-throughput proteomics platforms like SomaLogic and Olink that can measure thousands to tens of thousands of proteins in small blood samples. This allowed them to scale up the proteomic analysis. The researchers applied these proteomics platforms to large, longitudinal cohort studies. This provided them with blood samples and long-term dementia outcome data on thousands older adults. They identified a signature of five-year incident dementia using the SomaScan platform, and potential therapeutic targets, including SVP1.
Following up
However, focusing on older adults isn’t enough to gain a thorough understanding of dementia risk. In light of this, the team carried out a follow-up study on middle-aged adults.
By measuring proteins from this cohort, they were able to identify a proteomic signature of 25-year dementia risk in middle-aged adults. The study involved measuring 5,000 proteins in 11,000 blood samples from 1993 and relating them one-by-one to dementia risk over a 25-year period. They identified 30 proteins significantly associated with future dementia risk; some of these biomarkers have been nominated as therapeutic targets.
The proteins were then organised in 19 ‘modules’ based on co-expression. These modules themselves were then assessed for their link to future risk, four of which were highly significant. Moreover, of the proteins identified, GDF15 was taken forward for further analysis due to its strong links to dementia risk. This further research showed that, when combined with age, it is an effective predictor of vascular dementia.
What next?
The research identified midlife biomarkers for Alzheimer’s specifically, and dementia more broadly. This gives a better understanding of the underlying biology of these conditions and can be used to stratify patients and facilitate personalised approaches to treatment and prevention.
Check back soon to hear what Keenan had to say about cognitive resilience in individuals harbouring Alzheimer’s risk variants!
