Do Lipids Hold the Key to Blood-Based Alzheimer’s Test?

Researchers have long been searching for a blood-based test that could predict Alzheimer’s disease. In the March 9 Nature Medicine, researchers led by Howard Federoff at Georgetown University Medical Center, Washington, D.C., and Mark Mapstone at the University of Rochester School of Medicine, New York, report that a panel of 10 lipids could one day fit the bill. In a small study, plasma levels of these lipids distinguished, with 90 percent accuracy, who would develop cognitive impairment over the next two to three years. If the results are confirmed in larger samples, it would encourage hopes for a blood test for Alzheimer’s. However, the authors stress that is still years away. Numerous questions remain, including whether the observed lipid changes are specific to AD, or represent a more general marker for neurodegeneration. Despite this, the findings have generated excitement in the popular press, with numerous outlets touting the test as a potential AD diagnostic (see CNN story; Los Angeles Times story; USA Today story). 

Other researchers praised the study’s careful methodology, while cautioning that the data are still preliminary. “It’s a great proof-of-concept,” said Sid O’Bryant at the University of North Texas Health Science Center, Fort Worth. “We need to do more research on lipids. I think this sets the stage for a more comprehensive approach that incorporates [measures of] lipids and proteins, as well as other modalities.”

Previous research into plasma markers failed to identify a reliable diagnostic for AD (see Jun 2013 webinar). A small 2007 study reported that a panel of 18 blood proteins predicted progression to AD in a population of people with mild cognitive impairment (see Oct 2007 news story), but scientists say no replication of this finding has been published. A Finnish study found a set of plasma markers that correlated with heightened risk of dementia over 20 years, but the sensitivity was too low to make a good diagnostic test (see Kivipelto et al., 2006). Meanwhile, longitudinal studies such as the Australian Imaging Biomarker and Lifestyle (AIBL) study have turned up numerous blood biomarkers that distinguish people with AD from healthy controls in cross-sectional studies, suggesting that a blood test has potential (see Doecke et al., 2012; Burnham et al., 2013). 

Federoff and colleagues focused on finding markers that could spot Alzheimer’s disease before any symptoms appeared. They started with a pool of 525 healthy people, aged 70 and older, who were mostly well-educated, middle-class Caucasians from the Rochester area. They followed participants for five years, taking blood samples and administering cognitive tests at baseline and yearly follow-up visits. Over the course of the study, 28 of the participants developed either amnestic mild cognitive impairment (MCI) or AD. The authors randomly selected 18 of these 28 and looked for plasma markers in baseline samples that differentiated them from 53 controls who stayed healthy. Controls were matched for age, sex, and level of education. An initial broad analysis of metabolites revealed that levels of several plasma phospholipids showed the greatest difference between the groups.

Follow-up statistical analyses of these phospholipids identified eight phosphatidylcholines and two acylcarnitines as the best combination panel. At baseline, levels of all 10 were lower in the blood of people who went on to develop MCI or AD than in those who remained healthy. To validate the test, the authors applied it to a blinded sample of 40 additional participants, including the remaining 10 of the 28 whose cognition deteriorated. The assay classified the cognitively impaired and controls with 90 percent sensitivity and specificity. “This is one of the first reports of a plasma assay that detects preclinical disease with a high rate of accuracy,” Mapstone said.

“This is a very good study and an exciting advance,” said Eugenia Trushina at the Mayo Clinic in Rochester, Minnesota. She noted several strengths, including the fact that participants were well-matched for age and abstained from taking medications on the day blood was drawn. Aging and medication are both known to affect lipid profiles. A recent study of plasma and cerebrospinal fluid (CSF) AD markers by her group turned up many of the same metabolites (see Trushina et al., 2013). “I think they are on the right track,” she said.

Researchers agreed, however, that the findings must be validated in a larger, independent study. O’Bryant suggested that at least 200 people who progressed to cognitive impairment would be needed to be reasonably sure of the findings. The authors plan to test the assay in a much larger cohort, ideally several thousand people, Mapstone told Alzforum. Simultaneously, they hope to determine whether this assay can be used to select people with preclinical AD for upcoming prevention trials. Validation could be done in the placebo arm of such a trial, Mapstone suggested.

The study raises many questions. Commentators wondered how well the test would translate to other populations. Fats in the bloodstream vary with diet, ethnicity, and socio-economic status, suggesting that further research should look at more diverse populations, O’Bryant said. Henrik Zetterberg at the University of Gothenburg, Sweden, pointed out that the apolipoprotein E gene did not show up as an Alzheimer’s risk factor in this cohort, though it is well established that it is one. As a lipid chaperone, ApoE might be expected to influence levels of these molecules, suggesting that future studies should look for a possible connection between ApoE genotype and plasma lipids, Zetterberg said.

Why might lipid levels fall in the blood of people developing AD? This puzzles researchers. The lipids in question populate cell membranes, hence their levels might be expected to rise in the brain and CSF as neurons die and membranes break down. “We don’t believe we are measuring direct neuronal constituents,” Mapstone said, noting that these molecules do not cross the blood-brain barrier. “We don’t understand the biology yet.” Other studies have also seen less phosphatidylcholine in plasma and more in the CSF of AD patients compared to controls (see Schaefer et al., 2006; Walter et al., 2004). 

Perhaps the biggest question is whether other degenerative brain diseases might share a similar signature. The authors plan to test the panel in several diseases to answer this. They will also analyze protein, gene, and gene transcript data from the current study to see if adding additional factors could further improve the assay. “We’re hoping to put together a systems biology approach to diagnosing the disease,” Mapstone said.—Madolyn Bowman Rogers.

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References

Webinar Citations

  1. Webinar: O Blood-Based Biomarker, Where Art Thou?

News Citations

  1. A Blood Test for AD?

Paper Citations

  1. Kivipelto M, Ngandu T, Laatikainen T, Winblad B, Soininen H, Tuomilehto J. Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. Lancet Neurol. 2006 Sep;5(9):735-41. PubMed.
  2. Doecke JD, Laws SM, Faux NG, Wilson W, Burnham SC, Lam CP, Mondal A, Bedo J, Bush AI, Brown B, De Ruyck K, Ellis KA, Fowler C, Gupta VB, Head R, Macaulay SL, Pertile K, Rowe CC, Rembach A, Rodrigues M, Rumble R, Szoeke C, Taddei K, Taddei T, Trounson B, Ames D, Masters CL, Martins RN, . Blood-Based Protein Biomarkers for Diagnosis of Alzheimer Disease. Arch Neurol. 2012 Jul 16;:1-8. PubMed.
  3. Burnham SC, Faux NG, Wilson W, Laws SM, Ames D, Bedo J, Bush AI, Doecke JD, Ellis KA, Head R, Jones G, Kiiveri H, Martins RN, Rembach A, Rowe CC, Salvado O, Macaulay SL, Masters CL, Villemagne VL, . A blood-based predictor for neocortical Aβ burden in Alzheimer's disease: results from the AIBL study. Mol Psychiatry. 2013 Apr 30; PubMed.
  4. Trushina E, Dutta T, Persson XM, Mielke MM, Petersen RC. Identification of altered metabolic pathways in plasma and CSF in mild cognitive impairment and Alzheimer's disease using metabolomics. PLoS One. 2013;8(5):e63644. PubMed.
  5. Schaefer EJ, Bongard V, Beiser AS, Lamon-Fava S, Robins SJ, Au R, Tucker KL, Kyle DJ, Wilson PW, Wolf PA. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol. 2006 Nov;63(11):1545-50. PubMed.
  6. Walter A, Korth U, Hilgert M, Hartmann J, Weichel O, Fassbender K, Schmitt A, Klein J. Glycerophosphocholine is elevated in cerebrospinal fluid of Alzheimer patients. Neurobiol Aging. 2004 Nov-Dec;25(10):1299-303. PubMed.

External Citations

  1. CNN story
  2. Los Angeles Times story
  3. USA Today story

Further Reading

Primary Papers

  1. Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR, MacArthur LH, Hall WJ, Fisher SG, Peterson DR, Haley JM, Nazar MD, Rich SA, Berlau DJ, Peltz CB, Tan MT, Kawas CH, Federoff HJ. Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med. 2014 Apr;20(4):415-8. Epub 2014 Mar 9 PubMed.

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