Identification of a new plasma biomarker of Alzheimer's disease using metabolomics technology

Abstract

We performed unbiased analysis of steroid-related compounds to identify novel Alzheimer's disease (AD) plasma biomarkers using liquid chromatography-atmospheric pressure chemical ionization-mass spectroscopy. The analysis revealed that desmosterol was found to be decreased in AD plasma versus controls. To precisely quantify variations in desmosterol, we established an analytical method to measure desmosterol and cholesterol. Using this LC-based method, we discovered that desmosterol and the desmosterol/cholesterol ratio are significantly decreased in AD. Finally, the validation of this assay using 109 clinical samples confirmed the decrease of desmosterol in AD as well as a change in the desmosterol/cholesterol ratio in AD. Interestingly, we could also observe a difference between mild cognitive impairment and control. In addition, the decrease of desmosterol was somewhat more significant in females. Receiver operating characteristic (ROC) analysis between controls and AD, using plasma desmosterol shows a score of 0.80, indicating a good discrimination power for this marker in the two reference populations and confirms the potential usefulness of measuring plasma desmosterol levels for diagnosing AD. Further analysis showed a significant correlation of plasma desmosterol with Mini-Mental State Examination scores. Although larger sample populations will be needed to confirm this diagnostic marker sensitivity, our studies demonstrate a sensitive and accurate method of detecting plasma desmosterol concentration and suggest that plasma desmosterol could become a powerful new specific biomarker for early and easy AD diagnosis.

Fig. 1.

Extracted ion chromatograms in the positive-ionization mode of m/z 367.3 and 369.3 of age-matched control sample (A) and standards of five isomers (B).

Fig. 2.

Correlation between the values of desmosterol in human plasma and the desmosterol/cholesterol ratio in CSF (n = 43).

Fig. 3.

Comparison of plasma desmosterol level in all patients (A), male (B), and female (C). And comparison of plasma desmosterol/cholesterol ratio in all patients (D), male (E), and female (F). *P < 0.05, ***P < 0.001, n.s., not significant.

Fig. 4.

ROC plot analysis using plasma desmosterol value (A) or plasma desmosterol/cholesterol ratio (B) in AD (n = 41) versus control (n = 42). And ROC plot analysis using plasma desmosterol value (C) or plasma desmosterol/cholesterol ratio (D) in MCI (n = 26) versus control (n = 42).