Unique CSF lipid signature in asymptomatic subjects with a parental history of Alzheimer’s disease and its association with key apolipoprotein species

Abstract

AbstractBackgroundCSF apolipoproteins exhibit lipid‐specific relationships (signatures) with Alzheimer’s disease (AD) pathological markers and APOE‐ε4 in asymptomatic individuals.MethodMass spectrometry‐based CSF lipid analysis was performed as described before (Sampaio et al. 2011). Lipids were extracted using a one‐step chloroform/methanol procedure. After extraction, resulting samples were analyzed by direct infusion on a QExactive mass spectrometer equipped with a TriVersa NanoMate ion source. Both MS and MSMS data were combined to monitor CE, DAG and TAG ions as ammonium adducts; PC, PC O‐, as acetate adducts; and CL, PA, PE, PE O‐, PG and PI as deprotonated anions. CSF levels of amyloid beta (Aβ42), and total Tau (t‐Tau) were measured by enzyme‐linked immunosorbent assay (Fujirebio, Sweden) whereas apolipoproteins (AI, AII, B, CI, CII, CIII, D, E and J) concentrations were assessed using the Luminex/Biorad assays kit (10‐plex magneto‐fluorescent immunoassays, BioRad, USA).ResultsTo characterize human CSF lipid signatures and their relationship to several apolipoproteins in pre‐symptomatic AD, we profiled and analyzed 21 classes of lipid species (for a total of 796 sub‐species) and 10 apolipoproteins in 120 cognitively unaffected subjects exhibiting various levels of total tau, p(181)tau and Aβ42. Figure 1 illustrates the signature profile (after FDR correction) following stratification by APOE‐ε4 genotype at the time of recruitment, when no cognitive deficit was detected. Please note the preferential associations between phosphatidylethanolamine acetate species and apoB levels in the CSF in non‐ε4 carrier. The apoD‐lipid signature profile was found to be very different in ε4 versus non‐ε4 carriers. Figure 2 illustrates the different associations between lipid species and the different apolipoproteins found in the CSF as a function of AD severity (stratified using the CSF T‐Tau/Aβ42 ratio). As ratio increases (top tertile) and pathology unfolds, the lipid signatures become markedly altered, with strong effects observed with apoB, apoD and apoJ interactions.ConclusionOur results suggest that early amyloid and tau pathologies modulate the release of specific lipid species in the CSF which alters their relationship with apolipoproteins in an APOE‐ε4‐dependent manner.