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

Background: Alzheimer's disease (AD) patients display alterations in cerebrospinal fluid (CSF) and plasma sphingolipids. The genotype increases the risk of developing AD.

Objective: To test the hypothesis that the genotype affects common sphingolipids in CSF and in plasma of patients with early stages of AD.

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

Results: homozygotes displayed lower levels of sphingomyelin (SM;  = 0.042), SM(d18:1/18:0) ( = 0.026), and Aβ ( < 0.001) in CSF than non- carriers. CSF-Aβ correlated with Cer(d18:1/18:0), SM(d18:1/18:0), and SM(d18:1/18:1) levels in homozygotes ( > 0.49;  < 0.032) and with Cer(d18:1/24:1) in non- carriers ( = 0.50;  = 0.025). CSF-Aβ correlated positively with Cer(d18:1/24:0) in MCI ( = 0.028), but negatively in SCD patients ( = 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 genotype (< -0.47;  < 0.039). Nevertheless, age and sex are stronger determinants of individual sphingolipid levels in CSF than either the 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 homozygotes than in non- carriers ( = 0.048 and 0.047, respectively).

Conclusion: The 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.