Cerebrospinal fluid sphingolipids and acid sphingomyelinase change with beta amyloid levels in Alzheimer’s disease (576.5)

Abstract

Background: Sphingolipids (SP) and sphingomyelinase (SMase) play a role in amyloid processing. Thus, their cerebrospinal fluid (CSF) levels may change with beta amyloid concentration in Alzheimer’s disease (AD).Methods: Using liquid chromatography tandem mass spectrometry, we identified SP classes and species in two CSF fractions: nanometer‐sized particles (NP) representative of brain membrane metabolism and the NP‐depleted supernatant fluid (SF) representative of interstitial metabolism. We compared SP levels and SMase activity between 70 cognitively healthy CH study participants, 40 participants with mild cognitive impairment (MCI), and 29 with probable AD.Results: CSF fractions are differentially enriched with the SP classes and molecular species. In AD, SP metabolism was altered in both CSF fractions. The NP fraction had the greatest change in sphingomyelin (SM) species: concentrations of three species [SM(34:2), SM(34:1), SM(35:1)] were lower in AD and three [SM(34:2), SM(40:1), SM(41:2)] were lower in MCI compared with CH controls. Acid SMase activity decreased by 44 % in AD and correlated positively with the amyloid β42 levels in CSF from CH controls.Conclusions: Altered SP metabolism in dementia combined with decreased acid SMase activity and its lost association with CSF amyloid β42 levels in AD underscore these as potential disease biomarkers, and acid SMase as a target for AD research.Grant Funding Source: L.K. Whittier and the Helen Posthuma Foundations