Extracellular RNA identifies new Alzheimer's biomarker

By Emily Hayes, The Science Advisory Board contributing writer

April 2, 2020 -- The association of extracellular RNA with upregulation of the phosphoglycerate dehydrogenase (PHGDH) gene may be a useful presymptomatic biomarker for Alzheimer's disease (AD), according to an article published in Current Biology on March 26.

Alzheimer's disease is a progressive brain disorder that leads to memory loss due to the formation of amyloid plaques and neurofibrillary, or tau, tangles in the brain. Researchers have identified a number of genes associated with AD, including apolipoprotein E (APOE), amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2).

Extracellular RNAs (exRNAs), or RNA fragments that exist outside of cells, are uniquely protected from RNA-degrading enzymes, and thus can be detected in a number of biological tissues and fluids. Working under the premise that certain RNAs are consistently upregulated in the brain regions coinciding with neuropathologic changes in AD patients, the researchers wanted to explore whether plasma exRNAs of known AD-associated genes were more abundant in AD patients compared with controls.

The group evaluated extracellular RNA in plasma samples from 35 study participants who had confirmed Alzheimer's disease based on postmortem pathological brain examinations and who had been followed for 15 years prior to death. Of the total, nine had not been symptomatic and served as controls. All of the participants were older than 70.

The results suggest that the overproduction of extracellular RNA and brain protein expression by the PHGDH gene is associated with presymptomatic Alzheimer's disease in older adults and has potential as a future screening tool, noted Dr. Edward Koo, a professor of neuroscience at the University of California, San Diego School of Medicine, and colleagues.

Out of the nine control patients, plasma PHGDH exRNA was increased in eight, even though the patients were stable in terms of their cognitive symptoms over the course of the 15-year follow-up period, the researchers found. Furthermore, the findings were supported by analyses of published datasets, which also showed an association between PHGDH and early Alzheimer's disease, according to the group.

Searching for alternative tests

The study was conducted to address an unmet need for a presymptomatic test for Alzheimer's disease, particularly a noninvasive and affordable method. The field of drug development for the disease has been marred by repeated failures -- yet hope remains that treatments could work if only the Alzheimer's disease had been caught early enough.

"Given the prodromal phase of approximately 15 years before onset of clinical symptoms, novel biomarkers of early AD development will greatly assist in providing diagnostic information in presymptomatic individuals," the authors wrote.

Testing of beta amyloid in plasma and tau in cerebrospinal fluid have been exciting advances, but such methods have not exhibited strong power in the presymptomatic phase of disease, the authors noted.

The results suggest that circulating extracellular RNAs "may be a class of overlooked molecules for assessing the expression of genes within the central nervous system," and there may be potential to expand blood biomarker development beyond beta-amyloid and tau proteins and peptides to a "wide range of genes that are activated during AD development," they wrote.

"This expansion is much needed for research of early indications of AD because the initial molecular changes may well predate the accumulation of toxic [beta amyloid] and tau species," Koo et al concluded.

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