Blood DNA methylation profiles may rate Parkinson’s dementia risk
Researchers say intervention strategies may be developed from their studies
Understanding and identifying epigenetic changes — those that affect gene activity without altering a gene’s DNA sequence — in blood samples from people with Parkinson’s disease and other neurological conditions may help assess the risk of dementia, two independent studies suggest.
In one study, changes in DNA methylation, one of the most common epigenetic modifications, in the blood were associated with levels of certain biomarkers of Alzheimer’s and Parkinson’s disease in the cerebrospinal fluid (CSF), which surrounds the brain and spinal cord. The research was led by Katie Lunnon, PhD, at the University of Exeter Medical School.
In the second study, led by Ehsan Pishva MD, PhD, at Maastricht University, researchers developed epigenetic risk scores based on DNA methylation profiles, which were able to predict the risk of cognitive decline and dementia onset in different groups of patients with neurological disorders.
“Our findings highlight the potential of using blood-derived epigenetic measurements as a noninvasive approach to assess dementia risk, paving the way for future studies to explore more personalized and preventive healthcare strategies in tackling cognitive impairment,” Pishva said in a university press release.
Results from the studies were published in Alzheimer’s and Dementia: the Journal of the Alzheimer’s Association.
While motor symptoms are the hallmark of Parkinson’s, patients may also develop cognitive problems, including dementia. Studies have estimated that up to 40% of people with Parkinson’s develop dementia, which is also a key feature of other neurodegenerative conditions, including Alzheimer’s. For this reason, identifying predictive markers of dementia is clinically relevant to inform monitoring and treatment decisions.
DNA methylation, which involves the addition of chemical tags called methyl groups to specific DNA regions, has been suggested to be involved in dementia.
Measuring biomarkers in blood
In the first study, “Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer’s disease in the EMIF-AD study,” researchers profiled blood samples from 885 people collected as part of the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study. Participants included people with Alzheimer’s and mild cognitive impairment, and those without the conditions, who served as controls.
The researchers investigated whether DNA methylation patterns in the blood were associated with alterations in 15 Alzheimer’s biomarkers in CSF that are commonly used to diagnose dementia.
While CSF is often used for measuring the levels of disease biomarkers, its collection requires an invasive procedure called lumbar puncture, or spinal tap. Assessing biomarkers in blood samples is easier and less expensive, two factors that led researchers to investigate if blood samples could be used instead to assess changes in DNA methylation.
The results showed alterations in the methylation profile of certain key genes were associated with changes in the levels of specific biomarkers of Alzheimer’s and other neurodegenerative disorders.
The most significant association was seen in the DNA methylation pattern of the CHI3L1 gene, which contains instructions for making the YKL-40 protein, a CSF marker of brain inflammation. Its levels have been found to be markedly increased in the plasma, or liquid part of blood, of patients with early Alzheimer’s and in the blood of those with Parkinson’s.
“We provide evidence that DNA methylation in CH13L1 … may … [alter] CSF YKL-40 protein levels,” the researchers wrote, adding that “future research should further explore how DNA methylation potentially mediates the … effect of genetic variation on CSF YKL-40 levels.”
Developing risk scores
In the second study, “Blood-based multivariate methylation risk score for cognitive impairment and dementia,” researchers developed epigenetic risk scores using blood DNA methylation patterns as a proxy for 14 known dementia risk factors. Among these were age and a history of heart disease, as well as lifestyle choices that can be modified, such as physical activity and diet.
Data on blood DNA methylation was extracted from the Exeter 10,000 project (EXTEND), which collects blood samples and health information from people with and without health conditions, and the EMIF-AD MBD study. These studies were used to develop the epigenetic risk scores, which were then tested in three other datasets containing data from elderly people, along with those with Alzheimer’s and Parkinson’s.
Results showed the epigenetic risk scores could predict the risk of cognitive decline and dementia onset, even at early stages.
“Our epigenetic risk score can improve the prediction of risk of cognitive impairment in different populations, marking a significant advancement in dementia research. The study, which involved advanced analysis of large epigenetic datasets from multiple independent dementia cohorts, found that the epigenetic risk score was a predictor of future cognitive decline in Alzheimer’s disease and Parkinson’s disease cohorts,” Pishva said.
“As DNA methylation profiles have previously been shown to be modifiable through lifestyle changes, the information provided by our model possibly allows for targeted intervention strategies, aimed at maximally reducing the patient-specific risk scores,” the researchers wrote, adding “future studies should investigate how, and to what extent, these [methylation profiles] can be best modified by, for example, lifestyle interventions.”
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