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Plasma Biomarker for Amyloid Correlates With Alzheimer’s Progression, Study Finds

LOS ANGELES—A plasma biomarker for predicting amyloid-beta (Abeta) burden in the brain correlates well with markers of Alzheimer's disease (AD) progression such as PET, functional MRI, and cognitive test scores, according to findings presented here at the Alzheimer's Association International Conference.

The findings' suggestion that the blood test can detect even low levels of amyloid deposition in cognitively normal people is a step toward the possibility of wider clinical use in diagnosis and prevention, the researchers said, but an independent expert pointed to some potential hurdles.

The test predicts amyloid in the brain by assessing the ratios in the plasma of three Abeta-related peptides. Earlier tests found it predicted high or low amyloid burden with an accuracy of about 90 percent when using Pittsburgh compound B PET (PiB-PET) as the standard.

In this study, 201 plasma samples were collected from people who were cognitively normal as well as from those who had mild cognitive impairment, Alzheimer's disease (AD), and non-AD dementia at three centers in Japan. They were grouped as amyloid-positive or amyloid-negative based on where they were in a cutoff point on PiB-PET and on visual interpretation of imaging by experts.

Researchers found that the plasma biomarker resulted in 88 percent accuracy, with a sensitivity of 92 percent and specificity of 85 percent. Several cases were near the PET cutoff point for positivity but didn't clear it, though they were deemed positive upon expert visual examination. When these cases were included in the assessment of the biomarker test, the performance improved, with an accuracy of 93 percent, a sensitivity of 91 percent and specificity of 94 percent, said Akinori Nakamura, MD, PhD, a researcher with the National Center for Geriatrics and Gerontology in Obu, Japan, who presented the findings.

"This biomarker may be able to detect very small amounts of local amyloid accumulation," Dr. Nakamura said.

When researchers looked specifically at 38 cognitively normal subjects, they found that those who were positive at baseline for amyloid deposition based on the plasma biomarker went on to further accumulate amyloid in future years, while those who had originally tested negative almost uniformly stayed below the threshold for negativity.

"The plasma biomarker showed that most of the biomarker positive cases are Abeta-accumulators," Dr. Nakamura said. "So this suggests that the plasma biomarker may reflect the speed of Abeta accumulation."

The correlation coefficients for the biomarker and functional MRI and performance on the Mini-Mental Status Examination (MMSE) were relatively small—below 0.5—but statistically significant (p=.0022 and p<.001, respectively).

Dr. Nakamura said he hopes that allowing amyloid deposition to be determined with the blood test in clinical trials, rather than using the more expensive PET imaging, will help keep costs down. Moreover, he said, the test could be potentially useful for diagnoses and check-ups that would indicate risk before dementia presents clinically.

Eric McDade, DO, associate professor of neurology at Washington University in St. Louis, said the researchers' case for the validity of the test is persuasive.

"The results reported here provide a relatively high level of confidence given that this is a relatively well characterized population with an amyloid PET scan to provide confirmation of a significant level of amyloid plaque burden in the brain," he said. "The methods used for this plasma test are based on mass spectrometry and can provide sensitive measurements of the proteins, which are at very low levels in the blood."

While its practical application is "still limited," the potential is "very high," he said.

"What is most important is the ability to demonstrate that this method could be scaled up dramatically to be considered in a more community-based setting and to ensure that it is tested on a much broader population that will ensure the specificity of this method," Dr. McDade said.

"In order for a test to really be useful in a typical medical setting—for example, a primary care setting—it has to be demonstrated that the sensitivity and specificity remain relatively high in the presence of multiple medical conditions that might affect the outcomes of the test. Otherwise, its use might be limited to specialized clinics like a memory specialist."

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Nakamura A, Kaneko N, Villemagne VL, et al. High performance plasma amyloid-β biomarkers for Alzheimer's disease. Nature 2018; 554:249–254.