Plasma metabolites associated with clinically diagnosed Alzheimer’s Disease and the association is augmented using blood-based biomarkers.
Vrinda Kalia1, Dolly Reyes-Dumeyer1, Saurabh Dubey1, Renu Nandkumar1, Annie Lee1, Rafael Lantigua1, Martin Medrano2, Diones Rivera3, Lawrence Honig4, Richard Mayeux4, Badri Vardarajan4
1Columbia University, 2Pontificia Universidad Catolica Madre y Maestra, 3CEDIMAT, 4Columbia University Vagelos College of Physicians & Surgeons
Objective:

Identify metabolites associated with clinical diagnosis and pathology of Alzheimer's Disease (AD)

Background:
We investigated metabolites in plasma to capture systemic biochemical changes associated with AD diagnosed clinically and then using plasma biomarkers.
Design/Methods:

Exogenous and endogenous metabolites in plasma were measured in 300 clinical AD and 430 healthy non-demented individuals of Caribbean Hispanic ancestry using untargeted liquid-chromatography, performed on HILIC (+ ionization) and C18 (- ionization) columns, coupled to a Thermo Orbitrap HF-X mass spectrometer. Genome-wide SNP data and plasma biomarkers including Ab40, Ab42, P-tau181 and Neurofilament light chain (NfL) were obtained on all participants. Metabolite association with AD and P-tau181 levels were tested after adjustment for age and sex. Metabolites associated with P-tau181 levels (but not with NfL, a non-specific marker of neurodegeneration) were categorized as AD-specific.

Results:

Over 4000 metabolomic features were measured with high accuracy in the sample. 96 metabolites were associated with P-tau181 levels, but no metabolites survived multiple testing correction for association with clinical AD alone. Features putatively annotated as phosphatidylcholine (4.11E-07) and Carotamine (p=1.2e-05) were strongly associated P-tau181 levels. We observed similar results when using a diagnostic cutoff of P-tau181 levels for AD as the outcome. Metabolites associated with P-tau181 levels were enriched in amino acid metabolism, glutathione metabolism, tryrosine metabolism and hexose phosphorylation pathways. Ramipril (p=2.9e-04) and glycerophosphocholine (p=9.9e-04) were among the top associated with AD diagnosis. PLS-DA analysis identified biopterin metabolism, glycosphingolipid biosynthesis and tyrosine metabolism as the most discriminating pathways between AD and healthy controls when augmented by biomarkers.

Conclusions:

Metabolites specifically lipids and those involved in cardiovascular function were associated with AD and P-tau181 levels.  Metabolite profiling can identify perturbed pathways in clinical and pre-clinical AD and integration with genome-wide SNP data will identify mechanisms underlying genetic association with disease.

 

10.1212/WNL.0000000000203770