Lysophosphatidylcholines are associated with P-tau181 levels in early stages of Alzheimer’s Disease

Background: We investigated systemic biochemical changes in Alzheimer's disease (AD) by investigating the relationship between circulating plasma metabolites and both clinical and biomarker-assisted diagnosis of AD. Methods: We used an untargeted approach with liquid chromatography coupled to high-resolution mass spectrometry to measure exogenous and endogenous small molecule metabolites in plasma from 150 individuals clinically diagnosed with AD and 567 age-matched elderly without dementia of Caribbean Hispanic ancestry. Plasma biomarkers of AD were also measured including P-tau181, A{beta}40, A{beta}42, total tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Association of individual and co-expressed modules of metabolites were tested with the clinical diagnosis of AD, as well as biologically-defined AD pathological process based on P-tau181 and other biomarker levels. Results: Over 4000 metabolomic features were measured with high accuracy. First principal component (PC) of lysophosphatidylcholines (lysoPC) that bind to or interact with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and arachidonic acid (AHA) was associated with decreased risk of AD (OR=0.91 [0.89-0.96], p=2e-04). Restricted to individuals without an APOE {varepsilon}4 allele (OR=0.89 [0.84-0.94], p= 8.7e-05), the association remained. Among individuals carrying at least one APOE {varepsilon}4 allele, PC4 of lysoPCs moderately increased risk of AD (OR=1.37 [1.16-1.6], p=1e-04). Essential amino acids including tyrosine metabolism pathways were enriched among metabolites associated with P-tau181 levels and heparan and keratan sulfate degradation pathways were associated with A{beta}42/A{beta}40 ratio reflecting different pathways enriched in early and middle stages of disease. Conclusions: Our findings indicate that unbiased metabolic profiling can identify critical metabolites and pathways associated with {beta}-amyloid and phosphotau pathology. We also observed an APOE {varepsilon}4 dependent association of lysoPCs with AD and that biologically-based diagnostic criteria may aid in the identification of unique pathogenic mechanisms.