Multiomics profiling of human plasma and CSF reveals ATN derived networks and highlights causal links in Alzheimer's disease

INTRODUCTIONThis study employed an integrative system and causal inference approach to explore molecular signatures in blood and CSF, the Amyloid/Tau/Neurodegeneration [AT(N)] framework, MCI conversion to AD, and genetic risk for AD. METHODSUsing the EMIF-AD MBD cohort, we measured 696 proteins in cerebrospinal fluid (n=371), 4001 proteins in plasma (n=972), 611 metabolites in plasma (n=696) and genotyped data in whole-blood (7,778,465 autosomal SNPs, n=936). We investigated associations: molecular modules to AT(N), module hubs with AD Polygenic Risk scores and APOE4 genotypes, molecular hubs to MCI conversion and probed for causality with AD using Mendelian Randomization (MR). RESULTSAT(N) framework associated key hubs were mostly proteins and few lipids. In MR analyses, Proprotein Convertase Subtilisin/Kexin Type 7 showed weak causal associations with AD, and AD was causally associated with Reticulocalbin 2 and sphingomyelins. DISCUSSIONThis study reveals multi-omics networks associated with AT(N) and MCI conversion and highlights AD causal candidates.