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Initial Analysis of ADNI Plasma Proteome Data Suggests Possible Protein Signatures for Alzheimer's


By Adam Bonislawski

The Foundation for the National Institutes of Health's Biomarkers Consortium this week released data from a plasma proteomics study done by the Alzheimer's Disease Neuroimaging Initiative aimed at identifying blood-based protein biomarkers for diagnosing and monitoring the progression of Alzheimer's.

Preliminary analyses of the data have shown significant differences in protein expression between Alzheimer's patients and controls, said Holly Soares, director of clinical neuroscience biomarkers at Bristol-Myers Squibb and leader of the Biomarkers Consortium project team, suggesting that it may be possible to identify protein signatures in plasma indicative of the disease.

Because blood samples are significantly easier to obtain than cerebrospinal fluid, which is typically taken via a lumbar puncture, a plasma-based biomarker test could serve as a useful initial screen for the disease, Soares told ProteoMonitor. It could also provide drugmakers — a number of whom are currently engaged in Phase III trials for Alzheimer's therapeutics – with a way of selecting subjects that could be considerably less expensive than current methods like CSF analysis and PET scans, she said.

"We've done some top-line analysis, and there are many [proteins] that are significantly changed in [Alzheimer's] versus controls. We're seeing very interesting sorts of patterns," Soares said. "So that is promising. But it's still early days. We've only had two weeks to look through it."

The data comprises measurements of 189 proteins in blood from 600 subjects — normal, showing mild cognitive impairment, and with Alzheimer's — taken at the start of the project and one year later. The data was generated using Rules-Based Medicine's DiscoveryMap platform — a Luminex bead-based immunoassay measuring a broad range of proteins related to a variety of human disease.

The idea behind using the DiscoveryMap platform was to "look for the unexpected," John Trojanowksi, a researcher at the University of Pennsylvania School of Medicine and co-director of ADNI's Biomarker Core, told ProteoMonitor. "The [DiscoveryMap] panel of analytes isn't designed for the [central nervous system]. What we expect to find is perhaps something new that no one would have ever thought would reflect some aspect of Alzheimer's disease pathology."

He likened the effort to genome-wide association studies, "where people say, 'I've got a million SNPs across the human genome, and I'm going to interrogate people's DNA and see if I can find any hotspots in the genome that correlate with disease state.' It's exploratory."

Funding for the plasma proteome work was provided by a consortium of pharmaceutical companies through the Foundation for the National Institutes of Health. If data from the research is encouraging, the researchers will seek to conduct another study measuring protein levels at additional time points, Soares said.

"We haven't polled our members to see if the companies want to contribute additional dollars to do longer-term studies," she said. "But if it continues to look good, it's likely we'll do a second study with more time points."

The current climate is a difficult one for fundraising, Soares said, noting that "many of the major [pharmaceutical] players in the [Alzheimer's research] space are downsizing and really narrowing their portfolios, so there's not as much money as there used to be for these sorts of things."

There is, though, a "general commitment to try to find a blood-based test," she said. This stems in part from the industry's strategy with regard to Alzheimer's therapeutics, which relies on being able to identify patients at risk for progressing to dementia.

"People in dementia already have late-stage brain failure," Soares said. "It's too late to treat them very effectively because the pathology is very significant. So most of the field is moving towards treating [patients] before they're actually demented. And that's very difficult because that often looks like normal aging. It's very hard to identify those patients who just have memory deficits versus those who are really on the path to dementia."

Most likely, a plasma-based biomarker test would serve as a preliminary screen, she suggested, with patients flagged as being at high risk going on for more expensive, invasive procedures like MRIs, lumbar punctures, and PET scans.

"It's really kind of a staged process," she said. "That's how we're seeing the data shape up so far."

In addition to looking for plasma protein signatures, the researchers also plan to use results from the study to design the next stage of the project, which will try to identify protein biomarkers in CSF.

"The group is basically looking at the data now to determine which are the most potentially interesting proteins to look at in a CSF proteomic analysis," Neil Buckholtz, chief of dementias of aging at the National Institute on Aging, told ProteoMonitor. "They're trying to look at what are the most promising [proteins] based on the plasma analysis and then have those done by Rules-Based Medicine in CSF."

According to RBM vice president of corporate development Sam Labrie, the parties are still in negotiations regarding pricing for the analysis of the CSF set and haven't yet begun discussing what kind of cut-down panel might be used.

In addition to biomarker candidates, the CSF study could be helpful in identifying potential therapeutic targets, as well, Soares noted. The plasma work is less useful in this regard, but "once we understand the correlations between plasma and CSF and maybe even get some brain tissue in it, we'll have a better understanding of the [therapeutic] target space," she said.

ADNI is a research partnership supported primarily by the National Institute on Aging with 20 pharmaceutical companies providing private sector support through FNIH. The initiative comprises two primary approaches to mapping the progression of the disease — neuroimaging studies to track and define changes in the brain as individuals proceed from MCI to Alzheimer's and biomarker studies of plasma and CSF to track and define the same process. It was launched in 2004 with $40 million in funding from NIH and an additional $20 million provided by private industry partners. In October the program was renewed for another five years through late 2015.

All the data produced through the initiative is available to the public for download and analysis via the ADNI website.

Have topics you'd like to see covered in ProteoMonitor? Contact the editor at abonislawski [at] genomeweb [.] com.