Sphingolipids in Cerebrospinal Fluid and Plasma Lipoproteins of APOE4 Homozygotes and Non-APOE4 Carriers with Mild Cognitive Impairment versus Subjective Cognitive Decline

Sandra Den Hoedt, Kristien Y. Dorst-Lagerwerf, Helga E. De Vries, Annemieke J.M. Rozemuller, Philip Scheltens, Jochen Walter, Eric J.G. Sijbrands, Pilar Martinez-Martinez, Adrie J.M. Verhoeven, Charlotte E. Teunissen, Monique T. Mulder*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Alzheimer's disease (AD) patients display alterations in cerebrospinal fluid (CSF) and plasma sphingolipids. The APOE4 genotype increases the risk of developing AD. Objective: To test the hypothesis that the APOE4 genotype affects common sphingolipids in CSF and in plasma of patients with early stages of AD.


Patients homozygous for APOE4 and non-APOE4 carriers with mild cognitive impairment (MCI; n = 20 versus 20) were compared to patients with subjective cognitive decline (SCD; n = 18 versus 20). Sphingolipids in CSF and plasma lipoproteins were determined by liquid-chromatography-tandem mass spectrometry. Aβ42 levels in CSF were determined by immunoassay. 


APOE4 homozygotes displayed lower levels of sphingomyelin (SM; p = 0.042), SM(d18:1/18:0) (p = 0.026), and Aβ42 (p < 0.001) in CSF than non-APOE4 carriers. CSF-Aβ42 correlated with Cer(d18:1/18:0), SM(d18:1/18:0), and SM(d18:1/18:1) levels in APOE4 homozygotes (r > 0.49; p < 0.032) and with Cer(d18:1/24:1) in non-APOE4 carriers (r = 0.50; p = 0.025). CSF-Aβ42 correlated positively with Cer(d18:1/24:0) in MCI (p = 0.028), but negatively in SCD patients (p = 0.019). Levels of Cer(d18:1/22:0) and long-chain SMs were inversely correlated with Mini-Mental State Examination score among MCI patients, independent of APOE4 genotype (r< -0.47; p < 0.039). Nevertheless, age and sex are stronger determinants of individual sphingolipid levels in CSF than either the APOE genotype or the cognitive state. In HDL, ratios of Cer(d18:1/18:0) and Cer(d18:1/22:0) to cholesterol were higher in APOE4 homozygotes than in non-APOE4 carriers (p = 0.048 and 0.047, respectively).


The APOE4 genotype affects sphingolipid profiles of CSF and plasma lipoproteins already at early stages of AD. ApoE4 may contribute to the early development of AD through modulation of sphingolipid metabolism.

Original languageEnglish
Pages (from-to)339-354
Number of pages16
JournalJournal of Alzheimer's Disease Reports
Issue number1
Publication statusPublished - 3 May 2023

Bibliographical note

Funding Information:
This work was supported by grants to SdH, HEV, PMM, JW, and MTM from the ZonMw Memorabel program (project nr: 733050105). PMM is also supported by the International Foundation for Alzheimer Research (ISAO) (project nr: 14545).

Publisher Copyright:
© 2023 - The authors. Published by IOS Press.


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