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


Clark, Christopher; Dayon, Loïc; Masoodi, Mojgan; Bowman, Gene L; Popp, Julius (2021). An integrative multi-omics approach reveals new central nervous system pathway alterations in Alzheimer's disease. Alzheimer's Research & Therapy, 13(1):71.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute for Regenerative Medicine (IREM)
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Neurology
Health Sciences > Neurology (clinical)
Life Sciences > Cognitive Neuroscience
Language:English
Date:1 April 2021
Deposited On:03 Aug 2021 07:11
Last Modified:25 Feb 2024 02:41
Publisher:BioMed Central
ISSN:1758-9193
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1186/s13195-021-00814-7
PubMed ID:33794997
  • Content: Published Version
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)