In this population-based sample of older women, high serum ceramide levels (especially ceramides d18:1–C16:0, d18:1–C24:0, and lactosylceramide) were associated with an increased risk of all-cause dementia independent of age, blood glucose, and BMI. Importantly, the relationship between these lipids and AD was much stronger than for all-cause dementia, with an HR of about 10 and an apparent threshold effect. Only 1 person in the lowest tertile of serum ceramides d18:1–C16:0 and d18:1–C22:0 and lactosylceramide developed AD dementia. These findings suggest that high levels of serum ceramides increase the risk of developing AD.
Accumulating evidence suggests that ceramide metabolism may be perturbed early in the pathogenesis of AD.2,16,17,27
While the exact mechanisms by which this happens is an active area of research, a number of studies have identified pathogenic links between ceramides and amyloid-β (Aβ). First, exposure of cultured neurons to Aβ1–42
directly increases ceramide levels by activating neutral sphingomyelinase28–30
; inhibiting this ceramide production protects neurons from Aβ1–42
-induced cell death.16
indirectly increases ceramide production through an oxidative stress-mediated mechanism.16,31
Ceramides then increase inflammatory and reactive oxygen species, further enhancing the pathology in a self-sustaining way. Finally, increased levels of ceramides accelerate the formation of pathogenic forms of amyloid by increasing β- and γ-cleavage of APP.32–35
These results suggest that a disruption of ceramide metabolism may be an early and critical event involved in Aβ production and the neuronal dysfunction associated with AD.4
We have previously reported that high blood ceramide levels varied by AD severity and were predictive of cognitive decline and hippocampal volume loss among clinically adjudicated patients with amnestic MCI.18
The present study supports these findings by showing that high ceramide levels, particularly ceramides d18:1–C16:0, d18:1–C24:0, and lactosylceramide, are most strongly associated with an increased risk of AD dementia. Notably in previous shotgun and targeted studies of blood and brain ceramides,1,16,18,19
the ceramide d18:1–C24:0 has consistently been altered.
There was a threshold effect for both incident dementia and AD such that the HR of the highest tertile was similar or lower than the middle tertile. Thus, it is possible that low ceramide levels reduce the risk of dementia/AD, rather than that high levels are detrimental. Future studies with larger sample sizes are needed to better determine this threshold effect. Additionally, normal ceramide and SM levels have not been adequately established. Thus, we used tertiles because our data were in cycles per second, and not in easily quantifiable clinical units. Ongoing research is examining normal levels in the population and will be essential to define abnormal values, whether high or low, for risk of dementia and AD.
The exact mechanism by which blood ceramides could contribute to AD is currently unknown, but both direct and indirect mechanisms have been suggested.4
Among HIV-infected participants we have found a significant correlation between plasma and CSF ceramides,36
suggesting that there is a relation between blood measures of ceramides and brain levels. As HIV disruptions of the blood–brain barrier could be driving this association, additional research examining the blood–CSF relationship of sphingolipids in AD is ongoing. Indirect mechanisms may also contribute. Both ceramides and SM increase the risk of cardiovascular disease and insulin resistance,37–39
both of which are associated with an increased risk of AD. In the present study, we examined several vascular factors as mediators of the ceramide–AD relationship and found no attenuation of the relationship between serum ceramides and AD, but additional examination is needed in a larger study.
Several limitations warrant consideration. First, this sample was composed of women and may not be generalizable to men. However, there are currently no results from other studies to suggest the relationship should be different among men. Second, serum lipids were only assayed at baseline, leaving open the possibility that change in these biomarkers may be a better indicator of progression. Third, lipids were nonfasting and the effect of fasting on SM and ceramides is not clear. Correcting for fasting status by controlling for blood glucose had little effect on point estimates. Finally, while there was a high retention rate in this cohort (55.7% of the 436 participants completed all 6 examinations), over 9 years 90 participants died21
and some individuals were lost to follow-up (n = 103) and may have developed dementia, leading to a potential underdetection of cases and a conservative estimate of the lipid–dementia associations. The findings from this small study of women warrant replication in a larger population-based sample to verify the results.
Despite these limitations, there are several strengths. WHAS II is a longitudinal, population-based study that allowed us to examine the specificity of associations between blood SM and ceramides and incident dementia. Women had up to 6 examinations, and 9 years of follow-up. Second, dementia diagnoses were conducted via consensus conference and in collaboration with the Johns Hopkins AD Research Center. Finally, despite the small sample size, effect sizes were quite large and specific to ceramides.
In this preliminary study, high serum ceramide levels were associated with an increased risk of AD and warrant replication in a larger study. Additional research is also needed in larger studies to determine whether there are mediating vascular factors or whether the timing of the measurement (midlife vs late life) is important. The present results, combined with the current literature, call for additional examination into ceramide metabolites as potential new targets for the prevention or treatment of AD.