Sphingomyelin (SM) levels have been associated with Alzheimer’s disease (AD), but the association direction has been inconsistent and research on cerebrospinal fluid (CSF) SMs has been limited by sample size, breadth of SMs examined, and diversity of biomarkers available.
Objective:
Here, we seek to build on our understanding of the role of SM metabolites in AD by studying a broad range of CSF SMs and biomarkers of AD, neurodegeneration, and neuroinflammation.
Methods:
Leveraging two longitudinal AD cohorts with metabolome-wide CSF metabolomics data (n = 502), we analyzed the relationship between the levels of 12 CSF SMs, and AD diagnosis and biomarkers of pathology, neurodegeneration, and neuroinflammation using logistic, linear, and linear mixed effects models.
Results:
No SMs were significantly associated with AD diagnosis, mild cognitive impairment, or amyloid biomarkers. Phosphorylated tau, neurofilament light, α-synuclein, neurogranin, soluble triggering receptor expressed on myeloid cells 2, and chitinase-3-like-protein 1 were each significantly, positively associated with at least 5 of the SMs.
Conclusion:
The associations between SMs and biomarkers of neurodegeneration and neuroinflammation, but not biomarkers of amyloid or diagnosis of AD, point to SMs as potential biomarkers for neurodegeneration and neuroinflammation that may not be AD-specific.
WishartDS (2016) Emerging applications of metabolomics in drug discovery and precision medicine. Nat Rev Drug Discov15, 473–484.
2.
BainJR, StevensRD, WennerBR, IlkayevaO, MuoioDM, NewgardCB (2009) Metabolomics applied to diabetes research: Moving from information to knowledge. Diabetes58, 2429–2443.
3.
Puchades-CarrascoL, Pineda-LucenaA (2017) Metabolomics applications in precision medicine: An oncological perspective. Curr Top Med Chem17, 2740–2751.
4.
WikoffWR, PendyalaG, SiuzdakG, FoxHS (2008) Metabolomic analysis of the cerebrospinal fluid reveals changes in phospholipase expression in the CNS of SIV-infected macaques. J Clin Invest118, 2661–2669.
5.
IvanisevicJ, SiuzdakG (2015) The role of metabolomics in brain metabolism research. J Neuroimmune Pharmacol10, 391–395.
6.
WilkinsJM, TrushinaE (2018) Application of metabolomics in Alzheimer’s disease. Front Neurol8, 719.
7.
HanX, RozenS, BoyleSH, HellegersC, ChengH, BurkeJR, Welsh-BohmerKA, DoraiswamyPM, Kaddurah-DaoukR (2011) Metabolomics in early Alzheimer’s disease: Identification of altered plasma sphingolipidome using shotgun lipidomics. PloS One6, e21643.
8.
Pralhada RaoR, VaidyanathanN, RengasamyM, Mammen OommenA, SomaiyaN, JagannathMR (2013) Sphingolipid metabolic pathway: An overview of major roles played in human diseases. J Lipids2013, 178910.
9.
MielkeMM, LyketsosCG (2010) Alterations of the sphingolipid pathway in Alzheimer’s disease: New biomarkers and treatment targets?Neuromolecular Med12, 331–340.
10.
CrivelliSM, GiovagnoniC, VisserenL, ScheithauerA-L, de WitN, den HoedtS, LosenM, MulderMT, WalterJ, de VriesHE, BieberichE, Martinez-MartinezP (2020) Sphingolipids in Alzheimer’s disease, how can we target them?Adv Drug Deliv Rev159, 214–231.
11.
JohnsonSC, KoscikRL, JonaitisEM, ClarkLR, MuellerKD, BermanSE, BendlinBB, EngelmanCD, OkonkwoOC, HoganKJ, AsthanaS, CarlssonCM, HermannBP, SagerMA (2017) The Wisconsin Registry for Alzheimer’s Prevention: A review of findings and current directions. Alzheimers Dement (Amst)10, 130–142.
12.
MelahKE, LuSY-F, HoscheidtSM, AlexanderAL, AdluruN, DesticheDJ, CarlssonCM, ZetterbergH, BlennowK, OkonkwoOC, GleasonCE, DowlingNM, BratzkeLC, RowleyHA, SagerMA, AsthanaS, JohnsonSC, BendlinBB (2016) CSF markers of Alzheimer’s pathology and microglial activation are associated with altered white matter microstructure in asymptomatic adults at risk for Alzheimer’s disease. J Alzheimers Dis50, 873–886.
13.
HulleCV, JonaitisEM, BetthauserTJ, BatrlaR, WildN, KollmorgenG, AndreassonU, OkonkwoO, BendlinBB, AsthanaS, CarlssonCM, JohnsonSC, ZetterbergH, BlennowK (2021) An examination of a novel multipanel of CSF biomarkers in the Alzheimer’s disease clinical and pathological continuum. Alzheimers Dement17, 431–445.
14.
DarstBF, LuQ, JohnsonSC, EngelmanCD (2019) Integrated analysis of genomics, longitudinal metabolomics, and Alzheimer’s risk factors among 1,111 cohort participants. Genet Epidemiol43, 657–674.
15.
JohnsonSC, ChristianBT, OkonkwoOC, OhJM, HardingS, XuG, HillmerAT, WootenDW, MuraliD, BarnhartTE, HallLT, RacineAM, KlunkWE, MathisCA, BendlinBB, GallagherCL, CarlssonCM, RowleyHA, HermannBP, DowlingNM, AsthanaS, SagerMA (2014) Amyloid burden and neural function in people at risk for Alzheimer’s disease. Neurobiol Aging35, 576–584.
MajbourNK, ChiasseriniD, VaikathNN, EusebiP, TokudaT, van de BergW, ParnettiL, CalabresiP, El-AgnafOMA (2017) Increased levels of CSF total but not oligomeric or phosphorylated forms of alpha-synuclein in patients diagnosed with probable Alzheimer’s disease. Sci Rep7, 40263.
25.
KimYS, LeeKJ, KimH (2017) Serum tumour necrosis factor-α and interleukin-6 levels in Alzheimer’s disease and mild cognitive impairment. Psychogeriatrics17, 224–230.
LiuC-C, KanekiyoT, XuH, BuG (2013) Apolipoprotein E and Alzheimer disease: Risk, mechanisms, and therapy. Nat Rev Neurol9, 106–118.
36.
KulminskiAM, ShuL, LoikaY, NazarianA, ArbeevK, UkraintsevaS, YashinA, CulminskayaI (2020) APOE region molecular signatures of Alzheimer’s disease across races/ethnicities. Neurobiol Aging87, 141.e1–141.e8.
37.
MielkeMM, HaugheyNJ, HanD, AnY, BandaruVVR, LyketsosCG, FerrucciL, ResnickSM (2017) 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. J Alzheimers Dis60, 819–828.
38.
Pujol-LereisLM (2019) Alteration of sphingolipids in biofluids: Implications for neurodegenerative diseases. Int J Mol Sci20, 3564.
39.
DarstBF, KoscikRL, HoganKJ, JohnsonSC, EngelmanCD (2019) Longitudinal plasma metabolomics of aging and sex. Aging11, 1262–1282.
KoalT, KlavinsK, SeppiD, KemmlerG, HumpelC (2015) Sphingomyelin SM(d18:1/18:0) is significantly enhanced in cerebrospinal fluid samples dichotomized by pathological amyloid-β42, tau, and phospho-tau-181 levels. J Alzheimers Dis44, 1193–1201.
43.
JackCR, KnopmanDS, JagustWJ, PetersenRC, WeinerMW, AisenPS, ShawLM, VemuriP, WisteHJ, WeigandSD, LesnickTG, PankratzVS, DonohueMC, TrojanowskiJQ (2013) Update on hypothetical model of Alzheimer’s disease biomarkers. Lancet Neurol12, 207–216.
44.
ErminiL, AusmanJ, Melland-SmithM, YeganehB, RolfoA, LitvackML, TodrosT, LetarteM, PostM, CaniggiaI (2017) A single sphingomyelin species promotes exosomal release of endoglin into the maternal circulation in preeclampsia. Sci Rep7, 12172.
45.
MielkeMM, HaugheyNJ, BandaruVVR, ZetterbergH, BlennowK, AndreassonU, JohnsonSC, GleasonCE, BlazelHM, PuglielliL, SagerMA, AsthanaS, CarlssonCM (2014) CSF sphingolipids, β-amyloid, and tau in adults at risk for Alzheimer’s disease. Neurobiol Aging35, 2486–2494.
46.
CzubowiczK, JęśkoH, WencelP, LukiwWJ, StrosznajderRP (2019) The role of ceramide and sphingosine-1-phosphate inAlzheimer’s disease and other neurodegenerative disorders. Mol Neurobiol56, 5436–5455.
47.
(2019) Tier 1 metabolite identifications: A compass to rich research insights. Metabolon.
