Alzheimer disease: Plasma lipid biomarkers for early-stage Alzheimer disease

Nature Reviews Neurology 7, 474 (September 2011) [doi:10.1038/nrneurol.2011.125]

Changes in lipids in the brain have previously been associated with Alzheimer disease (AD). Now, an interdisciplinary team have used a multimodality lipidomics technique to measure hundreds of lipids simultaneously, and found significant changes in plasma lipids that are associated with the early stages of AD.

Animal models and postmortem analyses have identified alterations in specific brain lipids that are associated with the early stages of AD. Metabolomics—analysis of small molecules in cells and tissues—can characterize global signals of disease, but measurement in the brain is difficult, whereas peripheral plasma biomarkers are relatively easy to monitor.

Rima Kaddurah-Daouk and her colleagues aimed to analyze whether the plasma lipidome is altered in early AD, in order to “provide potential biomarkers for early diagnosis of AD, but also provide insights into the biochemical mechanisms underpinning the altered brain lipids.” AD treatments are most effective in the early stages, so biomarkers would also be useful for targeting therapeutic approaches.

In the first prospective study using multidimensional mass-spectrometry-based shotgun lipidomics, the researchers studied cellular lipids in plasma samples from 26 patients with mild or moderate AD and 26 controls. Nine lipid classes, 800 molecular species and the related pathways and networks of cellular lipids were analyzed.

The researchers focused on sphingolipids, and found that levels of eight of the 33 sphingomyelin species tested were significantly lower in patients with AD. Total sphingomyelin mass was also reduced, and ceramide content was increased. The ratios of sphingomyelin and ceramide species with identical fatty acyl chains were more-robustly able to discriminate groups than either metabolite alone.

Evidence regarding sphingolipids and AD has been inconsistent in the past, but these new results indicate that metabolomic changes vary with disease development.

The biochemical mechanisms leading to changes in peripheral blood lipids remain unknown, although it has been speculated that they are representative of changes in the brain. Kaddurah-Daouk says that she plans “to move the project forward through a study with both AD cases and apolipoprotein E genotypes using larger samples derived both centrally and peripherally. The research will move the project to both biomarker development and biochemical mechanism elucidation.”

This was a small study, and the results should be refined by further work with larger, more-diverse clinical samples. Lipidomics might be a promising new approach with which new biomarkers for AD can be identified, leading to new opportunities for treatment.

Eleanor Beal

References:

ORIGINAL RESEARCH PAPER

1. Han, X. et al. Metabolomics in early Alzheimer's disease: identification of altered plasma shingolipidome using shotgun lipidomics.
   PLoS ONE 6, e21643 (2011).