Non-target LC-HRMS to Study the Exposome of Mild Cognitive Impairment and Alzheimer’s Disease on Cerebrospinal Fluid

Alzheimer’s Disease (AD) is a complex and multifactorial neurodegenerative disease. The current diagnosis relies on non-specific biomarkers (Aβ1-42, t-Tau, and p-Tau) measured in cerebrospinal fluid (CSF), which do not provide sufficient insights into disease progression. Studying the exposome could reveal new disease-specific biomarkers for more accurate diagnosis. In this pilot study, exposomics was performed on the CSF of three groups; AD, Mild Cognitive Impairment (MCI) due to AD, and a non-demented control group (ND), using non-target high resolution mass spectrometry (NT-HRMS) coupled with liquid chromatography (LC). An open-source cheminformatics pipeline was developed using MS-DIAL and patRoon with PubChemLite for Exposomics, plus CSF- and AD-specific suspect lists. Fifteen statistically significant chemicals (nine Level l, six Level 2a) from diverse classes (amino acids, gut metabolites, sugars, environmental chemicals) were identified. Most of the relevant chemicals (thirteen out of fifteen) were detected using the Hydrophilic Interaction LC (HILIC) method. Environmental and lifestyle factors may explain some chemical differences found across groups, such as the higher levels of indole-3-acetic acid found in the AD and MCI compared to the ND group. This work provides a strong methodological basis and several promising hypotheses to upscale these efforts on larger AD cohort numbers in future studies.