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MicroRNA Expression Profiling Points to Possible Alzheimer's Signature in Blood

NEW YORK (GenomeWeb News) – Blood expression levels of a dozen microRNAs may help in distinguishing individuals affected by Alzheimer's disease from those who aren't, according to a study appearing online today in Genome Biology.

A German-led team used RNA sequencing to assess blood samples from 70 individuals with or without Alzheimer's disease. By narrowing in from the 140 differentially expressed miRNAs identified in that stage of the study, the group came up with a 12-miRNA signature that shows promise for detecting Alzheimer's disease.

When they used the miRNA set to test samples from hundreds more individuals, the researchers found that they could discern between the Alzheimer's disease cases and healthy controls with around 95 percent specificity and 92 percent sensitivity. The miRNA signature showed promise for telling Alzheimer's apart from other neurological conditions, too, they found, albeit with somewhat lower accuracy.

From their findings so far, the study's authors are hopeful that their miRNA profiling scheme may eventually lead to a non-invasive blood test for detecting Alzheimer's disease, which is currently diagnosed using cognitive testing and confirmed by autopsy.

"At present, there is no single molecular test that is suitable to reliably diagnose [Alzheimer's disease] with adequate specificity and sensitivity," co-senior authors Andreas Keller, a researcher affiliated with Saarland University and Siemens Healthcare, and Saarland University researcher Eckart Meese, and their colleagues wrote, noting that "additional work will be needed to elucidate the applicability of this 12-miRNA signature as a potential diagnostic test for [Alzheimer's disease]."

Past efforts to find biomarkers for Alzheimer's disease have looked at everything from genetic risk factors for the disease to cerebrospinal fluid levels of specific Alzheimer's-related proteins or peptide markers.

For the latest study, Keller, Meese, and colleagues opted to focus on miRNA levels in the blood, following research hinting that the expression of these molecules could change during Alzheimer's disease. If so, they reasoned that there may be advantages to profiling the molecules in easy-to-access blood samples.

The team used Illumina's HiSeq 2000 to sequence small RNAs in blood samples from 48 individuals with Alzheimer's disease and 22 unaffected control individuals.

When they compared the Alzheimer's patients with unaffected controls, the researchers detected expression shifts involving 140 unique mature miRNAs, including 82 miRNAs showing enhanced expression in blood samples from those with Alzheimer's disease and 58 found at lower-than-usual levels in the affected individuals' blood.

From there, they homed in on a candidate miRNA signature for Alzheimer's disease, comprised of 10 known miRNAs and two miRNAs not described in the past.

Through follow-up, real-time quantitative PCR-based tests, the team confirmed that expression profiles for the 12-miRNA set did cluster differently in blood samples from those with Alzheimer's compared to unaffected controls.

Because the group of 202 individuals assessed during that stage of the study included Alzheimer's disease cases as well as individuals with several other neurological conditions, the researchers also got a look at the miRNA signature's potential for distinguishing between different forms of neurological disease conditions — from schizophrenia or bipolar disorder to the mild cognitive impairment that precedes Alzheimer's disease development in some individuals.

Results of their analysis indicated that the test could differentiate between Alzheimer's disease and those sorts of neurological conditions with 74 percent to 78 percent accuracy — a dip from its 93 percent accuracy achieved when samples came only from Alzheimer's disease-affected individuals or healthy controls.

Perhaps more unexpectedly, the team found that the same miRNAs showed distinct blood expression patterns in individuals with neurological conditions such as major depression, bipolar disorder, and schizophrenia relative to healthy controls.

The test's performance in classifying individuals across the neurological disease spectrum is expected to improve as researchers continue refining the set of miRNAs included in their expression signature.

Even so, the study's authors cautioned that the diagnostic utility of the miRNA-based diagnostic test also hinges on further studies that take into account potentially confounding factors — from overlap between certain symptoms of Alzheimer's disease and other neurological conditions to patients' treatment regimens.

Along with the potential diagnostic implications of their results, those involved in the study noted that the Alzheimer's disease-associated miRNA expression patterns may also provide new information about the processes that go awry during the disease itself.

Among the 12 miRNAs that made it into the researchers' Alzheimer's signature, for instance, were miRNAs previously proposed to target genes involved in processes related to neuron and nervous system development.