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

Isoform- and cell-state-specific lipidation of ApoE in astrocytes

“…In line with this notion, we observed a significant accumulation of TAG in the brain of AD patients (data not shown). A very recent analysis of the cerebrospinal fluid (CSF) of a cohort of 120 elder subjects (with normal, mild cognitive impairment and AD) identified the presence of TAG(54:3) as being associated with the incipient phase and cholesteryl ester as being associated with the advanced phases of the disease (Clark et al, 2021). During the preparation of this manuscript, a series of elegant papers demonstrated the role of APOE4 in cellular TAG metabolism (Farmer et al, 2019;Qi et al, 2021;Sienski et al, 2021).…”

Integration strategies of multi-omics data for machine learning analysis

“… intNMF identified Glioblastoma and breast cancer subtypes from MO and clinical data [134]. MOFA/MOFA+ [141] , [142] Bayesian Factor Analysis biomarker discovery, systemic knowledge MOFA found new biomarkers and pathways associated with Alzeihmer’s disease based on MO data including proteomics, metabolomics, lipidomics [143] .MOFA + found predictive biomarkers from DNA methylation and gene expression data in cardiovascular disease [144] . iCluster [145] Gaussian latent variable model Generalized linear regression Bayesian integrative clustering Disease subtyping, biomarker discovery iCluster was used to identify subtypes of esophageal carcinoma from genomic, epigenomic and transcriptomic data [148] .…”

Advances in Proteomic and Metabolomic Profiling of Neurodegenerative Diseases

“…Interestingly, Xu et al (15) used an unsupervised learning approach to uncover lipid, protein, and gene expression levels in a cohort of ∼600 individuals and demonstrated integrated networks of lipids and proteins associated with AD, particularly those implicated in lipid metabolism and innate immunity. Furthermore, Clark et al (16) have recently conducted multi-omics analyses in the CSF of 120 elderly participants with normal cognition, mild cognitive impairment (MCI), and mild dementia. Their results proposed new pathways associated with AD, such as hemostasis, immune response, and extracellular matrix signaling.…”