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Biomarkers Show Promise for Classifying Those at Alzheimer's Risk

NEW YORK (GenomeWeb News) – A trio of cerebrospinal fluid biomarkers can accurately classify individuals who will develop Alzheimer's disease, according to a paper in today's issue of the Journal of the American Medical Association.

An international research team assessed the three CSF markers in 750 individuals with mild cognitive impairment to determine whether they could reliably predict progression to Alzheimer's disease. They also examined hundreds of individuals with Alzheimer's and healthy controls. Their findings suggest that, taken together, the biomarkers could pinpoint cases of incipient Alzheimer's with 83 percent sensitivity and 72 percent specificity. Nevertheless, those involved say it's too early to routinely use the biomarkers in the clinic.

"This multi-center study found that CSF Aß42, T-tau, and P-tau identify incipient [Alzheimer's disease] with good accuracy, but less accuracy than reported from single center studies," lead author Niklas Mattsson, a physician with Sweden's University of Gothenburg, and colleagues wrote. "Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures."

Along with research into APOE and other genes with potential diagnostic applications for Alzheimer's disease, researchers are actively pursuing biomarkers for finding and classifying individuals who are at elevated risk of Alzheimer's disease. Such markers could be particularly important down the road if effective Alzheimer's interventions are developed, Mattsson and his colleagues noted.

"The possibility that [Alzheimer's disease]-modifying treatment … or vaccination regimens will be developed raise a need for methods enabling early diagnosis," the authors explained. "Treatments would need to be initiated very early in the disease process, before the neurodegenerative process is too severe."

One potential source of biomarkers is CSF, the fluid that bathes the brain and spinal cord. Previous research suggests Alzheimer's patients tend to have higher than usual levels of a protein called tau, particularly in its phosphorylated form. In contrast, levels of the protein ß-amyloid or Aβ42 are often decreased in CSF from individuals with Alzheimer's. Consequently, some researchers have become interested in exploring the use of total tau (T-tau), phosphorylated tau (P-tau), and Aβ42 for their role as potential biomarkers.

Because previous studies of these biomarkers have been relatively small, Mattsson and his co-workers decided to look at their effectiveness for predicting Alzheimer's in a large study group, enrolling more than 1,500 individuals from a dozen European and American sites.

In the first stage of the study, the team determined the biomarker cutoff levels — the concentration of each biomarker estimated to provide at least 85 percent sensitivity — first by comparing Alzheimer's patients and healthy controls.

To test the biomarkers' predictive powers, the researchers focused on individuals with mild cognitive impairment — a condition characterized by cognitive decline that is beyond the normal levels for an individual's age but less serious than full-blown dementia.

Overall, the team looked at 750 MCI cases, 529 individuals with Alzheimer's disease, and 304 healthy controls.

Of the 750 subjects with mild cognitive impairment, 271 went on to develop Alzheimer's disease within two to 11 years of follow-up, while another 59 developed other forms of dementia.

As expected from smaller studies, T-tau and P-tau levels were higher — and Aβ42 levels were lower — in CSF from individuals with MCI who developed Alzheimer's, as measured by enzyme-linked immunosorbent assays of CSF collected by lumbar puncture.

Overall, the team's result indicated that the biomarkers as a group could detect underlying Alzheimer's in the MCI group with 83 percent sensitivity and 72 percent specificity using an equation that took into account T-tau as well as the Aβ42:P-tau ratio.

Even so, there were often differences in the levels of some biomarkers between the different testing sites, leading the authors to note that "considerable inter-center variations in assays and patient assessments … point to a need for standardization of sample handling as well as of clinical assessments."

"Cerebrospinal fluid biomarker changes were found to be significantly associated with incipient AD," the authors wrote. "However, the considerable inter-center variations in assays and patient assessments described point to a need for standardization of sample handling as well as of clinical assessments."

While the researchers noted that the biomarkers could have clinical implications in the future, they cautioned against using the biomarkers routinely in current clinical practice. "Until [disease-modifying Alzheimer's disease] treatments become available … these tests are not generally appropriate for routine clinical use because it is not currently possible to alter the development of [Alzheimer's disease]," the team concluded.

In an editorial appearing in the same issue of JAMA, Ronald Petersen, a researcher at the Mayo Clinic Alzheimer's Disease Research Center, and John Trojanowski, a researcher with the University of Pennsylvania's Alzheimer's Disease Core Center, called the study "an important contribution toward the goal of developing disease-modifying therapies based on the use of biomarkers and clinical measures."

But Petersen and Trojanowski also noted that "the study represents several key challenges that need to be addressed before CSF biomarkers are ready for broad clinical applications."

And though the pair acknowledged that some Alzheimer's biomarkers are already being studied in clinical trials, they, like Mattsson and colleagues, concluded that it's still too soon to use the biomarkers in a clinical setting.

"The investigators in this report are accomplished in [Alzheimer's disease] biomarker research and aware of the hurdles that need to be surmounted to bring an [Alzheimer's disease] biomarker from the initial discovery stage to a validated test for [Alzheimer's disease] diagnosis," they wrote. "The report highlights the challenges but also suggests solutions. Subsequent prospective investigations should clarify the true utility of these measures."

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