Lysophosphatidylcholines are associated with amyloidosis in early stages of Alzheimer’s disease

Circulating metabolites can identify biochemical risk factors related to Alzheimer's disease (AD). We measured plasma metabolites in 1,068 participants of Caribbean Hispanic ancestry (250 patients with AD and 818 healthy controls) across 2 cohorts and analyzed their relationship with clinical AD, biomarker-supported AD and plasma biomarkers (P-tau181, P-tau217, P-tau231 and Aβ42:Aβ40). Amino acid metabolism pathways were enriched among metabolites associated with P-tau biomarkers, whereas sialic acid and N-glycan pathways were associated with Aβ42:Aβ40. Through several dimensionality reduction approaches, we identified an APOE-ε4 dependent relationship between lysophosphatidylcholines (lysoPCs) carrying polyunsaturated fatty acids and biomarker-supported AD and P-tau biomarkers. In an independent dataset of 110 postmortem brain tissues from non-Hispanic white participants, lysoPCs in the brain were also associated with AD neuropathological features. Our results show that biomarker-based diagnostic criteria identified an APOE-ε4 dependent association with lysoPCs, which play a critical role in the transport of neuroprotective polyunsaturated fatty acids into the brain, and AD.