The Association Between Plasma Ceramides and Sphingomyelins and Risk of Alzheimer’s Disease Differs by Sex and APOE in the Baltimore Longitudinal Study of Aging

Abstract

Background Cellular and animal studies demonstrated relationships between sphingolipid metabolism and Alzheimer's disease (AD) pathology. High blood ceramide levels have been shown to predict cognitive impairment and AD, but these studies had small sample sizes and did not assess differences in risk by sex or APOE genotype. Objective To determine whether plasma ceramides and sphingomyelins were associated with risk of AD, and whether the association varied by sex and APOE genotype. Methods Participants included 626 men and 366 women, aged 55 years and older, enrolled in the Baltimore Longitudinal Study of Aging. Plasma ceramides and sphingomyelins were determined using quantitative analyses performed on a high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometer. Cox proportional hazards models, stratified by sex, were used to examine the relationship of plasma ceramides and sphingomyelins with risk of AD over a mean (SD) follow-up of 15.0 (7.0) years for men and 13.1 (5.9) years for women. Results Among men, the highest tertile of most ceramides and sphingomyelins were associated with an increased risk of AD. Among women, there were no associations between any of the ceramides and risk of AD. In contrast, women in the highest tertile of most sphingomyelins had a reduced risk of AD, which was most pronounced among APOE ε4 carriers. Conclusion These results provide further evidence for the role of sphingolipid metabolism in AD and highlight the importance of considering sex and APOE genotype in assessing this relationship.

Circulating ceramide ratios and risk of vascular brain aging and dementia

“…Some of these studies were limited by their cross‐sectional design or small sample sizes. In addition, results have varied across tertiles of ceramide levels and according to sex, with positive associations noted in women in one study, but only in men in a second study . To our knowledge, there have been no prior studies to date exploring the relationship between ratios of ceramides of varying fatty acyl chain length and the subsequent risk of dementia.…”

“…Previous studies have reported conflicting findings regarding the association between individual plasma ceramide species and the risk of AD dementia. Some studies have reported an association of both elevated long‐chain ceramides (C16:0) and very long‐chain ceramides (C22:0 and C24:0) with the risk of dementia or AD dementia, whereas others observed no association of very long‐chain ceramides with dementia risk. Some of these studies were limited by their cross‐sectional design or small sample sizes.…”

“…In addition, results have varied across tertiles of ceramide levels and according to sex, with positive associations noted in women in one study, 14 but only in men in a second study. 15 To our knowledge, there have been no prior studies to date exploring the relationship between ratios of ceramides of varying fatty acyl chain length and the subsequent risk of dementia. For each standard deviation, increment in the ratio of ceramides C24:0 to C16:0 and C22:0 to C:16:0, there was an approximate 25% lower risk of developing dementia in our investigation.…”

“…Total plasma ceramide concentrations have been suggested as potential early blood‐based biomarkers for predicting mild cognitive impairment and progression to dementia . Prior studies have reported an association between higher plasma ceramide concentrations and hippocampal atrophy, cognitive decline, as well as all‐cause dementia and AD dementia, although results have been conflicting between men and women . Additionally, many of these studies were limited by smaller sample sizes and a cross‐sectional design.…”

The Alzheimer’s Disease Metabolome: Effects of Sex andAPOEε4 genotype

“…Many metabolites affected by female sex, age, and APOE genotype(e.g., BCAAs, glutamate, lipids) appear altered in AD independent of these risk factors (16,17).MCI patients have alterations in lipid and lysine metabolism and the tricarboxylic acid cycle (18,19). We identified metabolic alterations in various stages across the trajectory of AD.…”