Ratio of Serum Very-long-chain to Long-chain Ceramides Is Predictive of Dementia Risk

Ceramides are a family of waxy lipid molecules composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer. Contrary to previous assumptions that ceramides and other sphingolipids found in cell membranes were purely supporting structural elements, ceramides have been shown to participate in a variety of cellular signalling roles: examples include regulating differentiation, proliferation, and programmed cell death.

Recently, attention has focused on the role of circulating ratios of a very‐long‐chain (C24:0, C22:0) to long‐chain (C16:0) ceramides as biomarkers for major vascular events and the possibility that these ratios may be of greater diagnostic and prognostic value for cardiovascular outcomes compared to total ceramide levels or concentrations of individual ceramide species. Furthermore, it has been hypothesized that the adverse cognitive effects of ceramides may be related to the relative proportions of circulating very long‐chain to long‐chain fatty acyl chains rather than simply due to elevated total ceramide levels.

To examine this hypothesis, investigators at Brigham and Women's Hospital (Boston, MA, USA) compared levels of very-long chain and long-chain ceramides in blood samples from 1,892 participants (mean age 70.1 years) in the Framingham Heart Study Offspring cohort. The investigators analyzed the risk of dementia, MRI structural measures of vascular brain injury, and beta-amyloid burden on brain PET (positron emission tomography) scans.

Results revealed that during a median 6.5 year follow‐up, 81 participants developed dementia, of whom 60 were diagnosed with AD dementia. Each standard deviation (SD) increment in the ratio of ceramides C24:0/C16:0 was associated with a 27% reduction in the risk of dementia and AD dementia. The ratio of ceramides C22:0/C16:0 was also inversely associated with incident dementia.

Very-long-chain fatty acyl ceramides are important for myelin function and may have a protective effect against dementia, while long-chain ceramide species are linked with deleterious pro-inflammatory and apoptotic effects. Therefore, circulating ceramide ratios may serve as potential biomarkers for predicting dementia risk in cognitively healthy adults.

"Our findings indicate that circulating ceramide ratios may be useful predictors of future dementia risk and may have a role in predicting dementia at an early, preclinical stage, when the greatest opportunity for disease modification exists," said first author Dr. Emer McGrath, associate neurologist in the department of neurology at Brigham and Women's Hospital. "However, these results will require replication in other cohorts."

The study was published in the January 16, 2020, online edition of the journal Annals of Clinical and Translational Neurology.

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