An integrative multi-omics approach reveals new central nervous system pathway alterations in Alzheimer’s disease

Abstract Background Multiple pathophysiological processes have been described in Alzheimer’s disease (AD). Their inter-individual variations, complex interrelations, and relevance for clinical manifestation progression remain poorly understood. We hypothesize that specific molecular patterns indicating both known yet unidentified pathway alterations are associated with distinct aspects of AD pathology. Methods performed multi-level cerebrospinal fluid (CSF) omics a well-characterized cohort older adults normal cognition, mild cognitive impairment, dementia. Proteomics, metabolomics, lipidomics, one-carbon metabolism, neuroinflammation related molecules were analyzed at single-omic level correlation regression approaches. Multi-omics factor analysis was used to integrate all biological levels. Identified analytes construct best predictive models the presence pathology decline multifactorial analysis. Pathway enrichment identified AD. Results integration five major dimensions heterogeneity explaining variance within differentially Further exposed multiple interactions between single ‘omics modalities multi-omics signatures amyloid pathology, neuronal injury, tau hyperphosphorylation. Enrichment revealed overrepresentation hemostasis, immune response, extracellular matrix signaling pathways association Finally, combinations four improved prediction (protein 14-3-3 zeta/delta, clusterin, interleukin-15, transgelin-2) cholesteryl ester 27:1 16:0 monocyte chemoattractant protein-1). Conclusions Applying an integrative approach we report novel These findings relevant development personalized diagnosis treatment approaches