Associations of plasma sphingomyelin SM (d18:1/24:0) with Alzheimer's disease pathology and cognition in non-demented adults

BackgroundPlasma sphingomyelin (SM), an established biomarker of white matter hyperintensity (WMH), has recently been implicated in Alzheimer's disease (AD) risk, but its role in cognitive decline remains unclear.ObjectiveTo examine whether plasma SM (d18:1/24:0) is associated with incident AD risk and to clarify its relationships with AD pathology, neuroimaging, and cognition in non-demented adults.MethodsWe included 476 non-demented participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Kaplan-Meier analysis assessed AD progression, with group comparisons by log-rank test. Cox proportional hazards models estimated hazard ratios and 95% confidence intervals. Multiple linear regression and mixed-effects models evaluated associations of SM with cerebrospinal fluid biomarkers, neuroimaging measures, and cognition. A causal mediation analysis was performed using 10,000 bootstrapped iterations to evaluate the intermediary role of AD pathology in cognitive function.ResultsParticipants with higher levels of SM (d18:1/24:0) exhibited decreased AD risk. Plasma SM (d18:1/24:0) presented positive associations with Rey Auditory Verbal Learning Test (RAVLT-immediate), amyloid-β pathology, ¹⁸F-fluorodeoxyglucose-positron emission tomography (FDG-PET) brain metabolism and brain volume, and negative associations with tau pathology, WMH-V, and ventricular volume. The association between SM (d18:1/24:0) and verbal memory was partially mediated by amyloid and tau pathology, FDG-PET, and hippocampal-V.ConclusionsThis study suggests that lower plasma SM (d18:1/24:0) levels are associated with an increased risk of AD. Plasma SM (d18:1/24:0) is closely related to cognitive performance, neuroimaging markers, and AD pathology, and its association with verbal memory may be partially mediated by AD pathology.