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New Alzheimer's Guidelines Call for Use of Protein Biomarkers in Clinical Research


By Adam Bonislawski

Workgroups led by the Alzheimer's Association and the National Institute on Aging this week published new criteria and guidelines for the diagnosis of Alzheimer's disease.

The guidelines, the first update from the groups in 27 years, propose the use of biomarkers including protein markers like Abeta1-42 and tau to classify patients for research purposes, marking the second publication in recent months to suggest that protein biomarkers be integrated into current definitions of Alzheimer's.

The first was published in October in The Lancet Neurology as a position paper from the International Working Group for New Research Criteria for the Diagnosis of Alzheimer's Disease (PM 10/15/2010). That paper called for a new definition of Alzheimer's that would allow for its diagnosis based on the presence of clinical symptoms, including hippocampal memory loss, plus the presence of protein and other biomarkers.

The guidelines released this week, which were published in the journal Alzheimer's & Dementia, similarly suggest that protein biomarker data be used to increase certainty of Alzheimer's diagnoses, particularly in the case of patients presenting with mild cognitive impairment, or MCI. Unlike the Lancet Neurology paper, however, the new proposal explicitly calls for protein biomarkers to be used only in research, not clinical, settings.

According to the proposed guidelines, a positive test for Abeta1-42 and a biomarker of neuronal injury like tau and phosphorylated tau indicate a high likelihood that MCI is due to Alzheimer's disease; a positive test for Abeta1-42 alone indicates an intermediate likelihood that MCI is due to Alzheimer's; and a negative test for both Abeta1-42 and neuronal injury biomarkers indicates a low likelihood that MCI is due to the disease.

As Bruno Dubois, professor of neurology at the Neurological Institute of the University Salpetriere Hospital and an author on the Lancet Neurology paper and co-author on the new AA/NIA guidelines, told ProteoMonitor in October, diagnosing patients early in the progression of Alzheimer's may improve the success of therapeutic approaches.

"Most of the [drug] studies that are negative today may be negative because the patients that are included in the trials are too late in the course of the disease," he said. "So this opens the window to include patients at the prodromal stage — they are clinically positive but not demented."

Several large pharmaceutical firms have recently reported disappointing results for Alzheimer's therapies. In August, Eli Lilly halted late-stage development of a compound called semagacestat after studies showed it actually made patients worse and was associated with an increased risk of skin cancer. Prior to that, in March, Pfizer announced that its Alzheimer's drug Dimebon appeared to be no better than a placebo at treating the disease.

According to Lon Schneider, director of the University of Southern California's State of California Alzheimer's Disease Research and Clinical Center, several drug trials currently ongoing have required that patients be positive for amyloid biomarkers, including one by Bristol-Myers Squibb and a phase II trial of an antibody therapeutic from an undisclosed pharma firm.

Questions remain, however, about how much value biomarkers add to conventional diagnoses that rely solely on measuring levels of cognitive impairment, Schneider, who was not involved in developing the new guidelines, told ProteoMonitor.

Data from the NIA's Alzheimer's Disease Neuroimaging Initiative showed that roughly 70 percent of 200 patients diagnosed with MCI due to Alzheimer's had positive cerebrospinal fluid levels of Abeta1-42, he said. The percentage positive for any Alzheimer's biomarker may approach 90 percent.

Measuring cognitive function at baseline, however, remains "more predictive of outcome than biomarkers, and the biomarkers add very little on top of" that measure, Schneider said.

"If you have a memory complaint score on [a memory test] below one and a half standard deviations of the norm, you're considered to have mild cognitive impairment” due to Alzheimer's, he said. "Now, 1.5 standard deviations is not that low, but if you've got a memory complaint and you score that low on a memory test and your activities of daily living are not too impaired, you're said to have MCI [due to Alzheimer's]. And people defined that way have a very high rate of developing Alzheimer's disease regardless of what their biomarker status is."

In fact, Schneider suggested, if the aim of early diagnosis is to identify people when therapy could be most useful, "it might be that the people who don't yet have positive biomarkers should be subject to early intervention, because it's maybe those people who are earliest in the process."

By requiring that patients be biomarker positive for inclusion in clinical trials, drug companies could be weeding out some of the sort of early-stage subjects the biomarkers are meant to help them capture, he said, noting that while currently "not all [clinical] studies require biomarkers, whether by next year the pharmaceutical companies will all jump off a cliff together and all require it for their studies remains to be seen."

The AA/NIA guidelines acknowledge the questions that still surround Alzheimer's biomarkers, noting that the proposed use of biomarkers is a "hypothetical framework" that "will need to be tested by future studies and revised, as future data are generated." In particular, it cites issues of cross-lab validation that have arisen with protein biomarkers like tau and Abeta1-42, noting that "standardization of these biomarkers is currently limited, and results often vary from laboratory to laboratory."

The guidelines also mention the potential for new CSF, plasma, and imaging markers for the disease. One of the larger efforts underway to search for such biomarkers is an ADNI project using Rules-Based Medicine's DiscoveryMap platform to look for plasma protein biomarkers tied to Alzheimer's. That study has looked at levels of 189 proteins in blood from 600 subjects — normal, showing mild cognitive impairment, and with Alzheimer's — and identified several protein signatures potentially linked to the disease (PM 12/10/2010).

UK-based proteomics firm Proteome Sciences has also developed a multiple-reaction monitoring mass spec assay to measure the levels of nine plasma protein biomarkers linked to Alzheimer's. The company debuted the test, which includes known potential biomarkers for the disease like ApoE and clusterin as well as new markers like gelsolin, alpha-2-macroglobulin, and complement factor H, in July 2010 and in February signed its first commercial contract for the panel with pharmaceutical firm Eisai (PM 02/04/2011).

"All this is good science. It makes sense," said Schneider of the field's biomarker pursuit. "But it's a work in progress."

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