Scientists uncover hidden links between brain diseases in precision medicine push

Scientists challenging conventional beliefs around the genetic risk factors for Alzheimer’s have discovered a genetic link behind a range of neurodegenerative diseases.

Westmead Institute Bioinformatics scientist Artur Shvetcov and neurodegenerative research head Caitlin Finney. Picture: Supplied

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A genetic biomarker long considered the leading biological risk factor for late-onset Alzheimer’s has been tied to a range of other cognitive diseases, helping scientists pursuing a cure to understand precise warning signs for how the brain degrades.

A machine learning study by the Westmead Institute for Medical Research and published in Nature Medicine used plasma and cerebrospinal fluid samples to gauge the correlation between Alzheimer’s and the genetic variant APOEε4, linking it not only to the common neurodegenerative condition but also to ALS, Parkinson’s and dementia.

A better understanding of the rates of correlation between APOEε4 and the various cognitive diseases helped them chart the contrary impact of lifestyle factors and genetic precursors.

The study linked the bio­marker to an elevated inflammatory response in the body that over many years could aggravate neurodegeneration. While the findings challenge the conventional understanding of Alzheimer’s disease, the study’s lead researchers hope it can pave the way for personalised medical interventions.

“The idea of precision medicine is to better understand someone’s genetic background and the environmental factors or variables that they’re exposed to and understand how those interact to lead to disease,” Westmead Institute neurodegenerative research head Caitlin Finney said.

“What our findings suggest is that people who have this APOEε4 genetic variant are ­biologically predisposed to be neurodegenerative, and this is because they have really high ­levels of inflammation and a dysregulated immune system.

“What we’re going to increasingly see is APOEε4 is great when you’re young and need to have a robust immune response to fight infections, stay healthy and reproduce, but as you age it’s probably not very good for you.”

The cross-sectional study involved 1346 cerebrospinal fluid and 9924 plasma samples sourced globally. A machine learning program was then used to identify the common proteins identified across the patient samples. It showed those carrying APOEε4 were far more likely to have Alzheimer’s disease, frontotemporal dementia, Parkinson’s, and ALS.

The Westmead Institute for Medical Research led the study. Picture: Supplied

Within APOEε4 carriers, however, proteins reacted differently to lifestyle factors. Those who smoked, drank or had high blood pressure were more likely to have a neurodegenerative ­disease than those with the biomarker who did not.

“While the presence of the APOEε4 genetic variant increases vulnerability to neurodegeneration, it is not sufficient on its own to cause disease. The signature we observed points to a chronic pro-inflammatory immune state that spans the plasma, cerebrospinal fluid, and brain,” study co-author Artur Shvetcov said.

Dr Finney said their research was part of a shift away from the prevailing theory behind Alzheimer’s – the amyloid hypothesis, which attributes neurodegeneration to the growth of harmful ­plaques between neurons.

“Our study is hopefully one more straw on the pile pushing away from the amyloid-beta (hypothesis) to try to look at other things,” she said,

“It took a step away from that single disease silo where we only operate in Alzheimer’s or we only operate in Parkinson’s. Operating like that overlooks important commonalities across diseases. When we start to understand those better, we’re going to be able to develop quicker and more widely applicable treatments.”

The study was backed by the Global Neurodegeneration Proteomics Consortium, a multidisciplinary research group con­vened by pharmaceutical giant Johnson & Johnson and philanthropic group Gates Ventures.

Dr Finney and Dr Shvetcov have already completed a follow-up to their study that is undergoing the peer-reviewing process. It links large-scale clinical findings back to the biological mechanisms behind Alzheimer’s, showing it is likely a precipitating cause of the disease.

“In this follow-up study we looked at Alzheimer’s specifically so we could track the development of what we call hallmark pathologies. We showed this pro-inflammatory phenotype starts well before those ­pathologies ­develop,” Dr Finney said.