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Structural Changes in Alzheimer's Biomarker Could Aid Early Detection of Disease


NEW YORK (360Dx) – A team led by researchers at the German Cancer Research Center and Ruhr University Bochum has identified a blood-based marker that can identify patients likely to develop Alzheimer's disease more than a decade before the onset of symptoms.

The test measures the commonly used Alzheimer's protein biomarker amyloid-β (Aβ), but instead of measuring levels of different Aβ isoforms as is typically done, it looks for structural changes in Aβ indicative of the disease.

In a study published last week in EMBO Molecular Medicine, the researchers found that these structural changes could identify patients who would go on to develop Alzheimer's an average of eight years before a clinical diagnosis was made.

The findings suggest the test could be useful for screening patients to identify those at high risk for Alzheimer's, said Klaus Gerwert, chair of biophysics at Ruhr University and an author on the study. He added that the approach could also prove useful in other diseases like Parkinson's where protein structural changes are involved.

The Aβ protein and its Aβ42 isoform, in particular, can cause amyloidosis in the brain in which the protein collects in plaques. Brain amyloidosis doesn't guarantee a person will develop Alzheimer's, but it is a significant risk factor for the disease. As such, measurement of Aβ42 levels in patient cerebrospinal fluid are commonly used, along with other markers and clinical factors, to diagnose Alzheimer's. Amyloid plaques are also a major target for Alzheimer's drug research with a number of agents intended to reverse or slow the development of these bodies.

Research has also shown that Aβ molecules undergo a change in their secondary structure in Alzheimer's patients, shifting from an α-helical to a β-sheet-enriched structure. This structural change is believed to be necessary for the protein to aggregate in the plaques characteristic of the disease.

These structural changes occur up to as many as 15 to 20 years prior to the onset of Alzheimer's, Gewert said, and so looking at these changes could allow for much earlier detection of the disease than is possible by looking at Aβ42 levels.

"This is a process that starts very early in the development of [Alzheimer's] disease," he said. "So we are directly observing the beginning of the pathological process."

To monitor these structural changes, Gewert and his colleagues developed an immune-infrared sensor that uses antibodies to Aβ to pull these proteins out of their sample of interest and then measures the distribution of the α-helical and β-sheet forms by observing the frequency shift in the infrared sensor. The proportion of α-helical versus β-sheet forms indicates whether a patient has a low or high risk of developing Alzheimer's.

The researchers tested the approach in a previous study looking at 141 patients with moderate-to-severe Alzheimer's, finding that it could diagnose patients with a sensitivity of 94 percent and specificity of 88 percent when looking at their CSF Aβ. Interestingly, they found the sensor was able to diagnose Alzheimer's based on plasma Aβ with a sensitivity of 75 percent and a specificity of 88 percent.

While the blood-based test was less accurate than the CSF test, its performance suggested it might, nonetheless, be useful as an initial screening test for Alzheimer's. Blood is much easier to collect than CSF, which requires a lumbar puncture. This makes a blood test highly desirable as a first-line screening tool where positive patients could be passed on to more accurate but more invasive and/or expensive tests like assays for CSF biomarkers or PET scans.

This is particularly an issue for clinical trials for Alzheimer's drugs where recruitment of patients with early-stage amyloidosis has proven a challenge. Asymptomatic patients are often reluctant to undergo a brain scan or spinal tap in order to join a clinical trial. A blood-based test could give drug researchers an easy way to do an initial scan of large numbers of patients with candidates identified by this test then passed on to imaging or CSF studies.

To follow up on the test's potential for assessing Alzheimer's risk by looking at Aβ structural changes in blood, Gewert and his colleagues investigated whether they could detect these changes in early-stage Alzheimer's patients. Looking in a set of 36 patients without dementia but with mild cognitive impairment and abnormal Aβ PET scans, they found their test could distinguish them from healthy controls with a sensitivity of 69 percent and specificity of 86 percent.

The researchers then investigated the test's performance in a cohort more representative of a general patient population, using plasma samples from the German ESTHER study, a longitudinal study following roughly 10,000 adults 50 to 74 years old. Looking at 65 patients diagnosed with Alzheimer's over the course of the study along with 101 diagnosed with other forms of dementia and 707 controls, the researchers found they could distinguish between Alzheimer's cases and controls with a sensitivity of 71 percent and specificity of 91 percent. Additionally, the average time between collection of the blood sample used for testing and the diagnosis of Alzheimer's was eight years, indicating the test can detect the disease well.

This level of performance, the authors noted, is not sufficient for a standalone diagnostic, but Gewert said it could be useful as a first-line screening test. He added that he and his colleagues are also working to improve the test's accuracy by refining the antibodies used in the test.

"At the moment we are just using commercial antibody," he said. "We are working hard to get an optimized antibody specifically tailored for our approach. We are testing at the moment several other antibodies, and we are quite confident that we can, with a new antibody, increase the sensitivity and specificity."

The researchers are also working to streamline and miniaturize the infrared sensing device used in the assay.

"The [EMBO Molecular Medicine] study was done with a Fourier-transform infrared spectrometer, which is quite large," Gewert said. But, he added, a newer version of the device is roughly the size of a cigar box.

"We are very confident that we will be able to bring an instrument to market within the next few years that can be [widely used] for a simple blood test," he said, adding that his lab has developed a prototype that is straightforward enough to be operated by non-expert users.

Gewert said he has several patents covering the approach and plans to form a startup to commercialize the technology. "That is the next step we would like to take," he said.