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Progression to Alzheimer's Predicted by Inflammation Plasma Proteins, Cardiff Team Finds


NEW YORK (GenomeWeb) – A team led by researchers at Cardiff University in the UK has identified several plasma protein markers that could be useful in identifying patients with mild cognitive impairment (MCI) who are likely to develop Alzheimer's disease.

Detailed in a paper published this month in the Journal of Alzheimer's Disease, the work focused on the complement system, an important inflammatory pathway that previous research has linked to Alzheimer's. In an analysis of 189 subjects with MCI, the researchers developed a three-protein panel that, when added to other clinical measures, identified patients who would progress to Alzheimer's within one year with a sensitivity of 80 percent and specificity of 79 percent.

The markers could prove useful for identifying patients in the earlier stages of the disease, initially for the purpose of clinical trials in drug development, suggested Paul Morgan, a Cardiff University researcher and the senior author of the paper.

Plasma protein markers are an area of keen interest within Alzheimer's research. The hope is that early detection markers could improve treatment efficacy by allowing clinicians to begin therapies before the disease has progressed significantly. Alzheimer's drug development efforts have had little success to date, with one line of thought being that drugs are being administered too late to have much effect.

Early detection markers are also key to putting together clinical trials where they could allow clinicians to better identify patients with MCI who are likely to progress to Alzheimer's.

Much of Alzheimer's biomarker research has used cerebrospinal fluid as a sample, but collecting CSF requires a lumbar puncture, which, Morgan noted, makes recruitment a challenge.

"If we want to sample relatively healthy individuals with MCI, sticking a needle in their spinal cord is not going to be acceptable," he said. This consideration has led a growing number of groups to look into plasma markers.

In many cases, these plasma marker studies have been relatively large-scale analyses. For instance, in 2012, a working group within the Alzheimer's Disease Neuroimaging Initiative used the Myriad RBMs Human DiscoveryMAP platform to measure levels of 190 plasma proteins in around 600 patients. Molecular neuropsychiatry firm Genomind has since licensed those markers.

Also, Proteome Sciences and King's College London have collaborated on large-scale plasma marker discovery efforts. In 2014, they published a study detailing a 10-protein panel stemming from those efforts that could help predict patients likely to progress from MCI to Alzheimer's.

The recent work by Morgan and his colleagues used a more targeted analysis, with the researchers focusing specifically on the complement pathway and measuring levels of 10 analytes involved in that inflammatory system.

The JAD authors noted that previous proteomic and genomic studies have identified potential links between the complement system and Alzheimer's. And the evidence that inflammation plays an important role in dementia "is growing all the time," Morgan said, adding that evidence is emerging that suggests a role for inflammation in the very early stages of the disease.

"So we decided to look at a part of the inflammatory system that we were very expert in, the complement system, to see whether we could pick up markers from the that system that were indicative of ongoing inflammation and might give us a handle on this question as to whether a patient with mild cognitive impairment would progress or not," he said.

In the study, Morgan and his colleagues using MSD's immunoassay platform to measure levels of their 10 analytes at baseline and one year later, finding that one protein, clusterin, was useful for diagnosing patients with Alzheimer's, and that a three-analyte panel consisting of clusterin, complement factor H (FH), and terminal complement complex (TCC) was able to identify patients who progressed from MCI to Alzheimer's.

Morgan called clusterin's ability to diagnose Alzheimer's patients "almost trivial," given that "once one has Alzheimer's, there is not really much that can be done about it." He did note, however, that this finding provided additional evidence that the complement system is involved in the disease.

Of greater interest was the three-protein predictive panel, Morgan said, adding that he and his colleagues have begun testing it in a larger cohort of patients and over longer periods of time.

He noted that the one-year period used in the JAD study was a relatively small window for observing progression from MCI to Alzheimer's. Nonetheless, during the course of the study, 26 percent of subjects developed Alzheimer's. This compares, the authors noted, to an average annual conversion rate of around 10 percent.

Sample sets show relatively large amounts of variation in terms of the percentage of patients converting, Morgan said. "You have a relatively small cohort; you get some noise; you have a different sort of patient collected. There are all sorts of reasons why there is variability in the rate of progression between cohorts."

The high rate of conversion among the Cardiff subjects could indicate a population tilted toward the more severe end of MCI, he said, though he added that there was no way of knowing whether that was in fact the case.

"All we have in terms of clinical assessment at the first sampling is 'no disease', 'mild cognitive impairment', or 'dementia'," he said. He added that he and his colleagues did not have data yet on how well the markers they identified were performing in the larger cohorts and over longer time courses.

Their work on inflammatory-based markers for Alzheimer's fits into a growing interest in tackling the inflammatory aspects of the disease, Morgan said, noting that he, in fact, came to the research through his interest in inflammatory processes.

Work has been done looking at the effect of anti-inflammatory drugs on development and progression of Alzheimer's, but many of these studies "are not terribly satisfactory," Morgan said, noting that they have typically looked not specifically at anti-inflammatories for treating Alzheimer's but at dementia in people who are also taking anti-inflammatories for other, unrelated conditions.

He said that he and his colleagues are interested in investigating what anti-inflammatory drugs might be effective in targeting specifically the forms of inflammation seen in MCI and early Alzheimer's.

Anti-inflammatory-based therapy "is now becoming a way of tackling the disease," he said. "But it hasn't gotten there yet."

He noted that he is also looking beyond inflammatory markers for predicting development of Alzheimer's.

"What we are now doing is taking other analytes that have been implicated, so things like tau, and anything else we can measure in plasma," he said. "I'm not fixated on complement."