Circulating ceramide ratios and risk of vascular brain aging and dementia.

Emer R Mcgrath,Charles Decarli,Daniel S Ory,Linda R Peterson,Vanessa Xanthakis,Meredith S Duncan,Jayandra J Himali,Sudha Seshadri,Ramachandran S Vasan,Alexa S Beiser,Claudia L Satizabal,Matthew P Pase,Jean E Schaffer

doi:10.1002/acn3.50973

Abstract

BackgroundWe determined the association between ratios of plasma ceramide species of differing fatty‐acyl chain lengths and incident dementia and Alzheimer’s disease (AD) dementia in a large, community‐based sample.MethodsWe measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia‐free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long‐chain (C24:0, C22:0) to long‐chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes.ResultsDuring a median 6.5 year follow‐up, 81 participants developed dementia, of whom 60 were diagnosed with AD dementia. In multivariable Cox‐proportional hazards analyses, 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 (HR 0.73, 95% CI 0.56–0.96) and AD dementia (HR 0.73, 95% CI 0.53–1.00). The ratio of ceramides C22:0/C16:0 was also inversely associated with incident dementia (HR per SD 0.75, 95% CI 0.57–0.98), and approached statistical significance for AD (HR 0.73, 95% CI 0.53–1.01, P = 0.056). Higher ratios of ceramides C24:0/C16:0 and C22:0/C16:0 were also cross‐sectionally associated with lower white matter hyperintensity burden on MRI (−0.05 ± 0.02, P = 0.02; −0.06 ± 0.02, P = 0.003; respectively per SD increase), but not with other MRI brain measures.ConclusionsHigher plasma ratios of very long‐chain to long‐chain ceramides are associated with a reduced risk of incident dementia and AD dementia in our community‐based sample. Circulating ceramide ratios may serve as potential biomarkers for predicting dementia risk in cognitively healthy adults.

Highlights

Discovering novel blood-based biomarkers for dementia can identify disease at an early preclinical stage, serve as surrogate outcomes for clinical trials of investigational therapies and inform our understanding of the underlying biological pathways of disease onset and progression
We investigated for interactions between ceramide ratios and sex, apolipoprotein E4 (ApoE4) carrier status and to high-density lipoprotein cholesterol (TC):HDL-C ratio (
In multivariable Cox-proportional hazards regression models adjusted for demographics, vascular risk factors, use of lipid-lowering therapies and ApoE4 carrier status, the ratio of ceramides C24:0/C16:0 was inversely associated with incident dementia (Hazards ratio [hazard ratios (HR)] per each standard deviation [SD] increment 0.73, 95% confidence intervals (CI) 0.56–0.96, P = 0.023) and Alzheimer’s disease (AD) dementia (HR 0.73, 95% CI 0.53–1.00, P = 0.050)

Summary

Introduction

Discovering novel blood-based biomarkers for dementia can identify disease at an early preclinical stage, serve as surrogate outcomes for clinical trials of investigational therapies and inform our understanding of the underlying biological pathways of disease onset and progression. We determined the association between ratios of plasma ceramide species of differing fatty-acyl chain lengths and incident dementia and Alzheimer’s disease (AD) dementia in a large, community-based sample. We related ratios of very long-chain (C24:0, C22:0) to long-chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Conclusions: Higher plasma ratios of very long-chain to long-chain ceramides are associated with a reduced risk of incident dementia and AD dementia in our community-based sample. Circulating ceramide ratios may serve as potential biomarkers for predicting dementia risk in cognitively healthy adults

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