Ceramides, which vary in the length of their carbon chains, make up the lipid portion of sphingolipids, including sphingomyelin. They have been linked in various ways to AD susceptibility and pathology. Higher ceramide levels crop up in people with early AD (see ARF related news story and Katsel et al., 2007). At the molecular level, Aβ42 stimulates sphingomyelinases that break down sphingolipids to release ceramide (see ARF related news story), and ceramide, in turn, stabilizes β-secretase, the enzyme that kickstarts Aβ production (see ARF related news story). Mielke and colleagues had previously linked AD severity to blood ceramides in cross-sectional analysis (see Mielke et al., 2010), but wanted to know if serum ceramide and sphingomyelins alter risk for future AD and/or all-cause dementia.

The researchers analyzed serum levels of ceramide, total sphingomyelin, and a variety of other lipids in 99 non-demented women aged 70-79, who had been followed in the WHAS II trial for up to nine years. During that time, 27 of the women developed dementia. Of those, 18 were diagnosed with probable AD. Splitting ceramide levels into tertiles, Mielke and colleagues found that women with the middle and highest levels of 16-carbon-long ceramide at the beginning of the study had up to a 10-fold higher risk of developing AD. Women with the highest tertile of C24 ceramide and lactosylceramide were also at substantially higher risk (5.1- and 9.8-fold, respectively). The hazard ratios were much higher than for all-cause dementia, suggesting a specific risk for Alzheimer’s.

How blood ceramides might increase the chances of getting AD is not clear, but both the authors and commentators noted connections between AD and cardiovascular disease. “It would be interesting to see which cardiovascular risk factors influence the production of ceramide in periphery, and whether available treatments for cardiovascular disease affect the associations between serum ceramide and dementia,” noted Haroutunian and Katsel.

In an accompanying Neurology comment, Valory Pavlik from Baylor College of Medicine, Houston, Texas, noted that “much work must still be done to replicate the findings in larger, more diverse samples, to determine which ceramide species are the most consistent predictors of risk, to establish optimal thresholds for predicting the outcome, and, most importantly, to understand the relationship between longitudinal variations in blood ceramide levels and the underlying pathologic processes of AD."

At the Alzheimer’s Association International Conference held 14-19 July 2012 in Vancouver, Canada, the variability in published blood-based biomarker studies was a prominent topic of discussion and poster presentations. Leading groups in the field are in the process of launching an international collaborative effort to standardize procedures so that independent replication of blood biomarker reports will be more possible in the future.—Tom Fagan.

References:
Mielke MM, Bandaru VVR, Haughey NJ, Fried LP, Yasar S, Varma V, Harris G, Schneider EB, Rabins PV, Bandeen-Roche K, Lyketsos CG, Carlson MC. Serum ceramides increase the risk of Alzheimer disease. Neurology. July 18 online. Abstract

Pavlik V. Serum ceramides—a new biomarker for preclinical AD? Neurology. July 18 online. Abstract