Can Small Molecules Provide Clues on Disease Progression in Cerebrospinal Fluid from Mild Cognitive Impairment and Alzheimer’s Disease Patients?

Alzheimer’s Disease (AD) is a complex and multifactorial neurodegenerative disease, which is currently diagnosed via clinical symptoms and non-specific biomarkers (such as Aβ1-42, t-Tau, and p-Tau) measured in cerebrospinal fluid (CSF), which alone do not provide sufficient insights into disease progression. In this pilot study, these biomarkers were complemented with small molecule analysis using non-target high resolution mass spectrometry (NT-HRMS) coupled to liquid chromatography (LC) on the CSF of three groups; AD, Mild Cognitive Impairment (MCI) due to AD, and a non-demented control group (ND). An open source cheminformatics pipeline based on MS-DIAL and patRoon was enhanced using CSF- and AD-specific suspect lists to assist in data interpretation. ChemRICH analysis revealed a significant increase of hydroxybutyrates in AD, including 3-hydroxy butanoic acid (BHBA), which was found at higher levels in AD compared to MCI and ND. Furthermore, a highly sensitive target LC-MS method was used to quantify 35 bile acids (BAs) in the CSF, revealing several statistically significant differences including higher dehydrolithocholic acid levels and decreased conjugated BAs levels in AD. This work provides several promising small molecule hypotheses that could be used to help track the progression of AD in CSF samples.