New Biomarker Offers Hope of Detecting Alzheimer's in Asymptomatic Stages

By Deborah Borfitz

July 10, 2024 | Until recently, all the available therapeutic options for treating Alzheimer’s disease were designed to reduce symptoms rather than address causes of the disease. But with two beta-amyloid antibodies now approved by the U.S. Food and Drug Administration, and tau-targeting agents in clinical trials, hopes are rising that Alzheimer’s progression can be delayed if not stopped. 

The ability to improve patient outcomes with biological treatments that attack the basis of the disease are dependent on many factors, not the least of which is early diagnosis, according to José Antonio del Río, full professor at the Faculty of Biology and the Institute of Neurosciences of the University of Barcelona and principal investigator at the Institute for Bioengineering of Catalonia. He was co-leader of a study, published recently in BBA Molecular Basis of Disease (DOI: 10.1016/j.bbadis.2024.167187), identifying a new biomarker of Alzheimer’s—a microRNA known as “miR-519a-3p”—in asymptomatic stages of the disease. 

The novel biomarker has been linked to changes in cellular prion protein known to be dysregulated in people suffering from some neurodegenerative diseases, including Alzheimer’s, with levels of it decreasing as the disease progresses. It remains unknown if selectivity of miR-519a-3p for Alzheimer’s can be extended to other neurodegenerative diseases, he says, but a similar phenomenon was not seen in postmortem studies of corticobasal degeneration, glial globular tauopathy, Pick's disease, and Parkinson's disease.  

The mechanism responsible for the changes seen in Alzheimer’s is not fully understood, but it has been observed that certain miRNAs bind to a specific region of the PRNP gene that controls cellular prion protein expression, says del Río in discussing the rationale for homing in on miR-519a-3p. Comparisons of previous studies and computational analyses in various genomic databases also pointed the research team in that direction. 

“Detection of miRNA is a complex molecular technique because it requires specificity in its detection and a relatively significant amount in the sample to be analyzed,” points out del Río. “In our case, the quantities present in brain parenchyma are sufficiently large to allow for effective detection.” Next steps include examining blood levels of the biomarker and whether measuring it is sufficient for making a differential diagnosis. 

Functional Studies

Numerous studies have looked at the presence of different miRNAs in neurodegenerative diseases, a subset of which has focused on their possible changes, del Río says. “To date, many of these studies have been merely descriptive, indicating a set of miRNAs that were more or less present in a disease.” 

The targets of these miRNAs are largely unknown as that requires functional studies, he continues. To that end, his lab conducted a study using databases in public repositories to learn which miRNAs present were binding to the messenger RNA of the prion protein “in its natural, non-pathogenic state.” 

Computational analysis of the potential interactions revealed a set of miRNAs, and from this list miR-519a-3p was plucked because changes in its expression were described in Alzheimer’s disease, explains del Río. “The pleasant surprise was that we could see its levels correlated with the changes that the natural prion protein undergoes during the development of [Alzheimer’s],” which he and his colleagues reported a few years ago.  

These earlier studies found “an increase [if the natural prion protein] at the onset of the disease and a decline in its expression that inversely correlates with the presence of pathogenic forms of tau and... mild cognitive impairment,” he says. “Indeed, both proteins exhibit an important interrelationship during the disease's development,” suggesting that detection of miR-519a-3p might aid in early detection of the disease. 

Disease Signature

In a forthcoming preclinical study, the research team will analyze miR-519a-3p in peripheral samples such as cerebrospinal fluid and then blood, del Río says. Its efficacy in signaling Alzheimer’s disease will be determined, with the findings extrapolated to other samples.  

Many samples from different cohorts will need to be analyzed to generate enough credible data for clinical trials to begin, he adds, as well as an understanding of other potential patient conditions such as diabetes or anti-inflammatory treatment. “To date, we know that miRNA is present in blood, but it remains to be reliably determined whether there are changes linked to [Alzheimer’s] and if they are reproducible.” 

Of course, miRNA alone cannot be used as a sole diagnostic tool, del Río says. “Like any molecule that shows changes in a disease,... [miR-519a-3p] must be included in a specific disease signature. Therefore, greater definition of its specificity is required, and we need to determine if this specificity at the peripheral level can match current levels of other markers such as pTau271, pTau181, neurofilaments, or even Aβ [beta-amyloid] in blood.” 

He and his team are optimistic that they can contribute to a peripheral signature of these markers that clinicians will find useful as a decision-making guide, says del Río. Early detection could significantly improve the diagnosis and treatment of Alzheimer’s, which affects more than 35 million people worldwide.