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Pair of Studies Show Plasma Protein Marker Could Aid Alzheimer's Disease Diagnosis

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NEW YORK – Two independent research teams have identifyied a phosphorylated form of the protein tau as a promising biomarker for the early detection of Alzheimer's disease.

In a pair of studies published this week, one in the Journal of Experimental Medicine and the other in the Journal of the American Medical Association, scientists found that plasma levels of phosphorylated tau-217 (p-tau217) correlated with p-tau217 levels in cerebrospinal fluid and could effectively identify patients either diagnosed with Alzheimer's or exhibiting the brain amyloidosis characteristic of the disease.

The fact that plasma p-tau217 levels appear to correlate well with measurements of the protein in CSF is notable in that previous studies have found CSF p-tau217 levels are able to detect the Alzheimer's as much as 20 years before the onset of symptoms and shortly after the initial development of amyloid plaques in the brain, said Nicolas Barthélemy, a researcher at Washington University in St. Louis and first author on the JEM study. Barthélemy is a member of the lab of Wash U neurology Professor Randall Bateman, senior author on the JEM study and a founder of C2N Diagnostics, which focuses on the development of diagnostics for neurodegenerative conditions including Alzheimer's.

"Knowing this really accurate biomarker exists in CSF, the question then was, 'OK, maybe this can also be recapitulated in some way in plasma,'" Barthélemy said.

Plasma biomarkers are an area of significant focus within Alzheimer's research. Total tau and phosphorylated tau are commonly measured in the CSF of patients suspected of having Alzheimer's as are amyloid biomarkers like amyloid-β42. These markers are also measured using positron emission tomography.

CSF and PET-based markers are poorly suited, however, to large-scale testing and particularly to screening of asymptomatic patients. Sample CSF requires a lumbar puncture, an invasive procedure that many patients, especially asymptomatic ones, wish to avoid. PET imaging, meanwhile, is an expensive and resource-intensive procedure. Blood-based markers offer the potential of a simpler, less invasive test for Alzheimer's.

P-tau217 is the most recent of several potential plasma markers to receive attention. Already C2N has presented data on its blood-based amyloid-β test indicating that it can predict the presence of amyloid plaques in the brain. The test, named the APTUS Aβ test, has received breakthrough device designation from the US Food and Drug Administration.

Barthélemy and his colleagues have also explored the use of p-tau181, which they evaluated along with p-tau217 in the JEM paper. Several of the JAMA study authors, including Oskar Hansson, professor of clinical memory research at Lund University and senior author on the study, have also investigated whether plasma p-tau181 could prove useful in diagnosing Alzheimer's. In March, Hansson and colleagues published a study in Nature Medicine showing that plasma p-tau181 levels were indicative of tau aggregates in the brain and linked to Alzheimer's.

The JEM authors found in an initial 36-subject discovery cohort that both p-tau217 and p-tau181 were highly effective at distinguishing between people with and without amyloid brain pathology, performing with an area under the curve (AUC) of .99 and .98, respectively. P-tau181's performance fell off when tested in a separate 92-subject validation cohort where it identified subjects with amyloid pathology with an AUC of .75. P-tau217, on the other hand, maintained good performance in this cohort, with an AUC of .92. The researchers also found that plasma and CSF measurements of both p-tau181 and p-tau217 were correlated.

The JAMA researchers looked at the performance of p-tau271 in 1,402 subjects from three different cohorts, finding that it could distinguish between patients with Alzheimer's disease and other neurodegenerative conditions with an AUC of .89 in patients whose condition was identified via neuropathology and .96 in patients diagnosed clinically. That performance, they noted, was better than existing plasma biomarkers and roughly equivalent to that of commonly used CSF and PET markers.

They also found that in carriers of the PSEN1 E280A mutation, which is a common cause of familial early onset Alzheimer's, p-tau217 levels were significantly higher than in non-carriers roughly 20 years prior to the carrier's onset of mild cognitive impairment.

A common challenge in measuring neurological biomarkers in plasma is sensitivity, as proteins present at relatively high levels in CSF may be present only at very low levels in plasma. To address this issue, the Wash U team developed a mass spec-based approach using upfront protein depletion and immuno-enrichment of tau protein in plasma followed by targeted mass spec. The JAMA researchers used an immunoassay run on the Meso Scale Discovery platform. The mass spec assay was more sensitive than the MSD assay, offering a limit of quantitation of .05 picograms per mL compared to a limit of detection of .48 pg/mL for the MSD assay.

However, Barthélemy noted that the mass spec assay required a relatively large sample size (20 ml of plasma in the discovery study and 4 ml in the validation study), which could present challenges in terms of obtaining samples for future work. He said the researchers were working to bring down the sample volume requirements.

Barthélemy said it was not yet clear whether p-tau217 could enable earlier detection of Alzheimer's than markers like amyloid-β as he and his colleagues have not yet done a longitudinal analysis looking at the marker. He said, though, that based on the behavior of p-tau217 in CSF, he believed plasma p-tau217 levels might change after amyloid-β levels but that the larger magnitude of the p-tau217 changes could make them easier to detect.

"That is going to be an interesting question to ask in the future," he said.

Earlier detection of Alzheimer's cases is of great interest to drug developers in particular as many believe the industry's failure to develop treatments for the disease is at least in part due to the fact that many patients have progressed too far by the time they receive the therapies. Pharma firm Eli Lilly developed the p-tau217 assay used in the JAMA study and several Lilly researchers were authors on the paper.

"As research progresses and we are able to identify AD earlier, we hope to tailor future treatment advances to the right patients at the right time," Jeffrey Dage, a senior research advisor at Lilly and study co-author, said in a statement.

The company said that it "will continue to optimize the assay and determine its potential role in clinical care."