“This is the first time that blood-based lipidomics has been used to describe an at-risk population in a neurodegenerative disease area,” Federoff told The Scientist.
This study “highlights the enormous potential of lipid biomarkers and their ability to predict memory impairment at a preclinical stage of Alzheimer’s disease,” said Columbia University’s Gilbert Di Paolo, an associate professor of pathology and cell biology, who was not involved in the work. That these biomarkers can be detected in the blood is particularly promising, he added. “The scientific community working on Alzheimer’s disease has explored this body fluid from many different angles to try and find biomarkers predicting the onset of this disorder, unfortunately without much success.”
The team followed 525 healthy participants, aged 70 and older, for five years. During that time, 74 of the participants met the clinical criteria for amnestic mild cognitive impairment or Alzheimer’s disease. Forty-six of the 74 were incidental cases at the outset, but 28 developed symptoms over the course of the experiment. Federoff and his colleagues focused on whether there were any metabolites that seemed to distinguish this latter group, so-called “converters,” in their metabolomic biomarker discovery efforts. And indeed, the researchers found that certain amino acids and phospholipids—which play key roles in the integrity and functionality of cell membranes—were, as they put it, “potent discriminators” of converters versus non-converters.
In a validation cohort of 40 participants, the team confirmed that this 10-metabolite panel was predictive of developing amnestic mild cognitive impairment or Alzheimer’s disease.
“[This study] is very interesting and certainly deserves more follow-up work and attention,” said Lesley Jones, a professor of psychological medicine and clinical neuroscience at Cardiff University in the U.K., who was not involved in the work. “It’s pretty clear that lipids play a role in Alzheimer’s disease and susceptibility, and there has been some genetic evidence [of this] as well, but we don’t really understand—mechanistically—how this operates at the moment.”
Because apolipoprotein E (APOE) is involved in lipid metabolism and its ε4 allele a known genetic risk factor for Alzheimer’s disease, the team sought to test the effects of APOE genotype on their lipidomic classification of converters versus non-converters. But the effect of the APOEε4 allele on this test appeared insignificant. And judging by APOE status alone, the researchers were unable to distinguish converter versus non-converters any better than they might have by chance.
“The result was interesting, insofar as APOE does not change the predictive accuracy of this test,” said Federoff.
The study builds upon researchers’ recent interests in unraveling the biochemical pathways behind neurodegeneration, said Rima Kaddurah-Daouk, an associate professor of pharmacometabolomics at the Duke Institute for Brain Sciences in Durham, North Carolina.
“We have speculated that [changes in] the lipids that are important for proper [cell] membrane structure and communication could really be a critical step in triggering the cascade of events leading to cognitive impairment and Alzheimer’s disease,” she said. “All of these observations—along with this wonderful new study that goes earlier in the disease process—confirm that it’s time to come back to the biochemistry in a very serious way.”
Federoff’s team would now like to see whether the results hold up in younger adults and more ethnically diverse participants. In the meantime, the researchers are analyzing genomic information in an effort to connect any apparent differences in gene expression to changes in lipid metabolism. “We’ve sequenced everyone, and although we haven’t fully analyzed [that data], we’d like to take [the metabolomics information] back to the genome, to see whether there any new pieces of information that could be helpful that would only be understood at the genomic level.”
“The tools have become available for us in metabolomics and lipidomics over the last decade to dive deep into the metabolic understanding of Alzheimer’s disease,” said Kaddurah-Daouk. It’s increasingly clear, she added, that “genetics alone are not sufficient.”
M Mapstone et al., “Plasma phospholipids identify antecedent memory impairment in older adults,” Nature Medicine, doi:10.1038/nm.3466, 2014.