- High blood levels of RNA produced by the PHGDH gene, which is critical for brain development and function, could serve as a biomarker for early detection of Alzheimer’s disease, a study published in Current Biology revealed.
The discovery could also lead to the development of a blood test to identify individuals who will develop the condition years before they show symptoms.
The PHGDH gene produces RNA and proteins that are critical for brain development and function in infants, children, and adolescents. When people get older, the gene typically decreases its production of these RNAs and proteins.
The findings of the study suggest that the overproduction of a type of RNA, called extracellular RNA (exRNA) by the PHGDH gene in elderly people could provide an early warning sign of Alzheimer’s disease.
“Several known changes associated with Alzheimer's disease usually show up around the time of clinical diagnosis, which is a little too late. We had a hunch that there is a molecular predictor that would show up years before, and that's what motivated this study,” said Sheng Zhong, a professor of bioengineering at the UC San Diego Jacobs School of Engineering.
Researchers developed a technique that is sensitive enough to sequence tens of thousands of exRNAs in less than one drop of blood. The method, called SILVER-SEQ, was used to analyze the exRNA profiles in blood samples of 35 elderly individuals 70 years and older who were monitored up to 15 years prior to death.
The subjects consisted of 15 patients with Alzheimer’s disease, 11 patients who were initially healthy and then later developed Alzheimer’s, and nine healthy controls.
The results showed a steep increase in exRNA production in patients who didn’t initially have Alzheimer’s, approximately two years before they were diagnosed with the condition. PHGDH exRNA levels were on average higher in Alzheimer’s patients. exRNA levels did not exhibit an increasing trend in the controls, except for one control who later developed Alzheimer’s.
While the results demonstrate the ability to identify potential Alzheimer’s disease patients using this particular blood biomarker, the researchers did note some limitations of the study.
“This is a retrospective study based on clinical follow-ups from the past, not a randomized clinical trial on a larger sample size. So we are not yet calling this a verified blood test for Alzheimer's disease,” said co-first author Zixu Zhou, a bioengineering alumnus from Zhong's lab.
“Nevertheless, our data, which were from clinically collected samples, strongly support the discovery of a biomarker for predicting the development of Alzheimer's disease.”
In future studies, researchers will test whether the PHGDH biomarker can be used to identify patients who will respond to drugs for Alzheimer’s disease. The team is also open to collaborating with Alzheimer’s research groups that may be interested in validating and testing this biomarker.
“If our results can be replicated by other centers and expanded to more cases, then it suggests that there are biomarkers outside of the brain that are altered before clinical disease onset and that these changes also predict the possible onset or development of Alzheimer's disease,” said Dr. Edward Koo, a professor of neuroscience at the UC San Diego School of Medicine.
“If this PDGDH signal is shown to be accurate, it can be quite informative for diagnosis and even treatment response for Alzheimer's research.”