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Newly Identified Blood Biomarkers Predict Conversion to Alzheimer's

Talan, Jamie

doi: 10.1097/01.NT.0000446540.49527.7d
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Researchers reported that 10 lipids from peripheral blood predicted phenoconversion to either amnestic mild cognitive impairment or Alzheimer's disease within a two- to three-year timeframe with over 90 percent accuracy.

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Researchers identified 10 lipids or fats that were powerful enough to predict phenoconversion to either mild cognitive impairment (MCI) or Alzheimer's disease (AD) within a two- to three-year study period with 90 percent accuracy.

While the findings emerged from a relatively small sample of patients, experts in the field told Neurology Today that the results, published online first on March 9 in Nature Medicine, are encouraging and should be replicated in larger data sets. Identifying preclinical AD disease with a blood test — much like screening for cholesterol for heart disease and/or stroke — could change the course of the disease for future generations of older people, they said.

Howard J. Federoff, MD, PhD, executive dean of Georgetown University School of Medicine, who led the research team, noted that others have identified potential blood markers but none have been replicated so far. The problem, he said, is that there are substantial circadian variations in metabolism and finding a true signature is difficult. Knowing that there are changes in metabolism and gene expression throughout the day and in response to eating and medication, the researchers added a critical design change to their study: they collected blood after a night of fasting and before a person had any of his or her daily medications on board. He believes that this pure blood sample helped in the identification of these newly identified markers.

“I think that our success in identifying these markers is because of the way we looked at the blood and our collection method,” said Dr. Federoff.

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The researchers enrolled and monitored 525 healthy people for five years; all were at least 70 years old and were living independently in the community. Over the course of the study, 74 of them met criteria for MCI or mild AD. Forty-six had incidental MCI or AD when they entered the study and 28 had phenoconverted from a cognitively fit state to MCI or AD. The average time to phenoconversion was 2.5 years. The scientists had a control group of age-, gender-, and education-matched cognitively normal people.

Using tandem mass spectrometry to identify metabolites, the researchers analyzed 124 plasma samples from 106 study participants. They were able to identify and qualify lipids, amino acids, and biogenic amines. Their hope was to be able to identify specific changes in the blood from the time people were cognitively normal to when they were diagnosed with memory problems; and to use the blood samples to differentiate between cognitively normal people, those who phenoconverted during the study, and those who had already shown signs of cognitive problems at entry into the study.

In the third year of the study, they selected 53 people diagnosed with MCI or AD whose blood would be screened for metabolomics and lipidomic biomarker discovery. Eighteen patients had converted during the observational period. They compared the findings with 53 people in the control group. They analyzed the blood from the converters on at least two time points — from the sample obtained at the time they entered the study to the blood draw collected after diagnosis. They used the last blood drawn from those in the control group.

Dr. Federoff said that the analysis showed significantly lower plasma levels of serotonin, phenylalanine, proline, lysine, phosphatidylcholines (PC), taurine, and acylcarnitines (AC) in the converters. They identified 10 lipids that were depleted in the converters and not the controls. To be sure of their findings, they performed the same blood analysis on 40 others and replicated the same panel of 10 biomarkers. These biomarkers are phospholipids that play a role in the structure and function of cell membranes.

The blood markers for the 10 lipids were lower in the group that had just phenoconverted than in those who had signs of AD at the start of the study. But the levels never returned to normal, even in the AD group.

“We posit that this ten-phospholipid biomarker panel…reveals the breakdown of neural cell membranes in those individuals destined to phenoconvert from cognitive intactness to amnesic MCI or AD, and may mark the transition between preclinical states where synaptic dysfunction and early neurodegeneration give rise to subtle cognitive changes,” the scientists wrote in the Nature Medicine paper.

They said that the “accuracy for detection is equal to or greater than that obtained from most published CSF studies.”

The researchers also looked at the effects of having at least one copy of the apolipoprotein E4 (APOE4) allele and it did not seem to make a difference on the changes that they identified in the blood samples.

“It is important now to replicate our findings,” said Dr. Federoff, who said that he began this observational study to see whether they could enroll cognitively normal older people and establish a neuropsychological battery that they could use to follow people over time and identify people at the earliest signs of memory trouble.

“Our data has led to a new set of biological insights,” Dr. Federoff added. “This is an area of biology we have to probe more deeply.”

AD researchers, who were not involved with the study, said that one of the major weaknesses of the study is that the group did not have brain scans that could corroborate a pathological diagnosis of MCI or AD. “It would have been great but we just didn't have the money,” said Dr. Federoff. He is now talking to other researchers who have blood tests and brain scans on their study subjects.

The researchers are also looking at the genetic signature from the blood profiles. “This is a compelling story and it must be expanded,” said Dr. Federoff.

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“This is an exciting finding but [it is] preliminary,” said Neil Buckholtz, PhD, director of the Division of Neurosciences at the National Institute on Aging (NIA). “We know from similar studies that something that shows up in one population may not show up in another. It needs replication.”

As for the panel identifying involvement of phospholipids, he added, “they are markers of healthy cell membranes and it makes sense that this could be part of the disease process.” He stressed that this is a long way “from a clinically useful blood test for Alzheimer's.”

Certainly, a blood test would be far less expensive than collecting cerebrospinal fluid or ordering a brain scan. “But so far the field has not had much success at finding things in blood that would predict AD,” added John Hsiao, MD, chief of the diagnosis and biomarkers for dementia program in NIA's Division of Neurosciences. “We hope it is as powerful as it seems. It tells us something about the pathology of AD and it may offer a tool to see something in the blood today that might predict symptoms years from now.”

David S. Knopman, MD, FAAN, a professor of neurology at the Mayo Clinic in Rochester, MN, and an expert on Alzheimer's biomarkers, said he believes that “the findings are overstated.” They offered no brain imaging to back up their findings, he said. “There might be some truth, but a lot more work needs to be done.” He is not so sure that what goes on in the brain doesn't stay in the brain.

Neither is Ronald C. Petersen, MD, PhD, director of the Mayo Clinic Alzheimer's Disease Research Center. Still, he said: “This [a blood test] is where we need to go. Alzheimer's is a public health issue and we need to have relatively simple non-invasive tests to see who is more likely to develop Alzheimer's. Developing a blood test for Alzheimer's is not a trivial task.”

Rima Kaddurah-Daouk, PhD, an associate professor of the pharmacometabolomics center at Duke University, sees the workings of metabolism at the very heart of every disease state. To that extent, she said, “to use these global approaches in metabolomics is a far more sophisticated way of understanding disease. It's as if you had a powerful telescope that is allowing you to see things that were not possible before.” Her work in Alzheimer's has also focused on identifying and mapping lipids.

“The beauty of this paper in Nature Medicine is that they used simple measures to identify chemistry. That allowed them to determine that there is a problem in lipid metabolism very early in the disease process, before symptoms emerge. This is a fantastic step forward. Having these tools will redefine a lot of things in the clinical field. Blood captures a lot of relevant information on pathological changes in the brain. It's no longer enough to think about the brain not being connected to the rest of the body.”

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•. Mapsonte M, Cheema AK, Fandaca MS, et al. Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med 2014; E-pub 2014 Mar. 9.
•. Sperling RA, et al. Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & Dementia: The Journal of the Alzheimer's Association 2011;7:280–292.
© 2014 American Academy of Neurology