Circulating inflammatory proteins predict dementia risk, are linked to structural brain changes and modifiable risk factors.

Comprehensive Summary

Although neurofibrillary inflammation in the body has been identified as a risk factor for neurodegeneration, it has not yet been proven that identifying inflammatory proteins can predict the risk of dementia in patients. To help identify this, a large-scale data set of about 500,000 people from the UK BioBank was used to analyze the relationship between inflammatory proteins and dementia. Participants of the study answered base-line questions about their health and lifestyle, and also underwent blood sampling and other genome-sequencing to help identify any risk factors. Protein biomarkers in the blood samples were measured through an antibody-based assay called Olink Explore 3072 technology. Machine learning was used afterwards to predict the proteomic signature (ProSig) of the inflammatory proteins, which were predictive of dementia in the patients. The ProSig was then compared to the brain image-derived phenotypes and the brain age to identify neurological markers signaling dementia risk. Then, specific inflammatory proteins were analyzed to see if they were the product of genetic risks or lifestyle factors, such as smoking or diabetes. Finally, a Mendelian randomisation technique was used to evaluate the causal relationship between the inflammatory proteins and dementia. Using 728 inflammatory proteins and their proteomic data, the study revealed that the subjects with dementia were older on average, more likely to be male, have unhealthy lifestyles, and be homozygous or heterozygous for the APOE-E4 alleles. Higher ProSign levels were strongly associated with an increased patient risk of dementia. Patients with high ProSig numbers showed accelerated brain aging and reduced brain age, illustrating that the brain structure is affected when inflammatory proteins are present. The randomisation techniques used in the study showed that some genetic and lifestyle factors were mediated by the inflammatory proteins. Overall, this study was able to show that inflammatory proteins were able to improve the prediction of dementia risk in patients.

Outcomes and Implications

"This study helped illustrate the way inflammatory mechanisms lead to neurodegeneration, and ways that biomarkers for neurodegeneration can be highlighted. This helps make a diagnosis in patients easier, and helps physicians identify ways to interfere with the disease early on in the prognosis. This gives patients a better chance at effective treatment. For future studies, researchers can evaluate whether certain anti-inflammatory drugs work to decrease the ProSig and can work as an effective treatment for neurocognitive decline. Overall, this study helped identify ways to predict dementia-risk patients by evaluating the inflammatory proteins present in their blood.