23 Jul 2012

Results of a nine-year longitudinal study indicate that women with the highest amounts of certain types of ceramide in their blood are more likely to develop Alzheimer’s disease. Researchers led by Michelle Mielke from the Mayo Clinic, Rochester, Minnesota, made the association by analyzing a subset of data from the Women’s Health and Aging Study II (WHAS II). They report the results in the July 18 Neurology online. Commentators urged caution in interpreting the findings because of the small sample size of only women. If the results hold up in larger studies, the lipids might become prodromal markers for AD. “That the current study identified these alterations in blood is compelling, and points to the potential role of cardiovascular risk factors in dementia and its progression,” wrote Vahram Haroutunian and Pavel Katsel, The Mount Sinai School of Medicine, New York, in a comment to Alzforum (see below).

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

Comments

1. • Vahram (Harry) Haroutunian
     The Mount Sinai School of Medicine
   • Posted: 23 Jul 2012
   • Paper: Serum ceramides increase the risk of Alzheimer disease: the Women's Health and Aging Study II.

   A recent longitudinal population-based study of older women by Mielke et al. showed that high serum ceramide levels were associated with an increased risk of all-cause dementia independent of age, blood glucose, and BMI. These findings are consistent with results of previous postmortem brain studies where total ceramide content has been found to be increased even in cases with mild cognitive decline, and the ceramide mass increase has been attributed to longer acyl chain ceramide species (1). These findings are also supported by the gene expression changes within the canonical sphingolipid metabolism pathway during the earliest recognizable stages of AD (2).

   Given the strong evidence of interactions between glucosphingolipids and amyloid-β, their regulation of amyloid-β production, and their role in the cellular survival pathways, it is not surprising to see early changes in ceramide levels during the progression of AD. That the current study identified these alterations in blood is compelling, and points to the potential role of cardiovascular risk factors in dementia and its progression. A majority of epidemiologic studies support a role for cardiovascular disease and cerebral ischemia as risk factors for AD. Microvascular dysfunction is a prominent underlying cause of silent strokes that are not in themselves symptomatically recognized, but may cumulatively represent a major contributor to cognitive impairment in elderly persons (3). It would be interesting to see which cardiovascular risk factors influence the production of ceramide in the periphery, and whether available treatments for cardiovascular disease affect the associations between serum ceramide and dementia. The current findings also have a potential for the development of convenient and accurate peripheral biomarkers of prodromal AD.

   References:

   Han X, M Holtzman D, McKeel DW, Kelley J, Morris JC. Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer's disease: potential role in disease pathogenesis. J Neurochem. 2002 Aug;82(4):809-18. PubMed.

   Katsel P, Li C, Haroutunian V. Gene expression alterations in the sphingolipid metabolism pathways during progression of dementia and Alzheimer's disease: a shift toward ceramide accumulation at the earliest recognizable stages of Alzheimer's disease?. Neurochem Res. 2007 Apr-May;32(4-5):845-56. PubMed.

   Schwartz E, Wicinski B, Schmeidler J, Haroutunian V, Hof PR. CARDIOVASCULAR RISK FACTORS AFFECT HIPPOCAMPAL MICROVASCULATURE IN EARLY AD. Transl Neurosci. 2010 Jan 1;1(4):292-299. PubMed.

   View all comments by Vahram (Harry) Haroutunian

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References

News Citations

1. ApoE Primer: News on Sulfatide and Insulin Links, Synaptic Damage and Molten Globules 17 Jan 2003
2. A Better GRIP on the Aβ-Lipid Connection 17 Oct 2005
3. Ceramide Leads to Higher BACE Levels 4 Apr 2003

Paper Citations

1. Katsel P, Li C, Haroutunian V. Gene expression alterations in the sphingolipid metabolism pathways during progression of dementia and Alzheimer's disease: a shift toward ceramide accumulation at the earliest recognizable stages of Alzheimer's disease?. Neurochem Res. 2007 Apr-May;32(4-5):845-56. PubMed.
2. Mielke MM, Haughey NJ, Ratnam Bandaru VV, Schech S, Carrick R, Carlson MC, Mori S, Miller MI, Ceritoglu C, Brown T, Albert M, Lyketsos CG. Plasma ceramides are altered in mild cognitive impairment and predict cognitive decline and hippocampal volume loss. Alzheimers Dement. 2010 Sep;6(5):378-85. PubMed.

Further Reading

News

1. Ceramide Leads to Higher BACE Levels 4 Apr 2003
2. ApoE Primer: News on Sulfatide and Insulin Links, Synaptic Damage and Molten Globules 17 Jan 2003
3. A Better GRIP on the Aβ-Lipid Connection 17 Oct 2005