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An integrative multi-omics approach to investigate cerebral and systemic biological pathway alterations with clinical relevance in early Alzheimer’s disease

English title An integrative multi-omics approach to investigate cerebral and systemic biological pathway alterations with clinical relevance in early Alzheimer’s disease
Applicant Popp Julius
Number 204886
Funding scheme Project funding
Research institution Gerontopsychiatrisches Zentrum Psychiatrische Universitätsklinik Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurophysiology and Brain Research
Start/End 01.12.2021 - 30.11.2025
Approved amount 969'350.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Neurology, Psychiatry

Keywords (6)

Brain volumetry; Alzheimer Disease; Biomarkers; Multiomics; Disease Mechanism; Systems Biology Approach

Lay Summary (French)

Lead
A part la pathologie amyloïde et la neurodégénérescence liée à la protéine tau, de multiples changements biologiques sont associées à la maladie d’Alzheimer. Les causes et conséquences cliniques de ces changements sont encore méconnues.
Lay summary

Contenu et objectifs du travail de recherche : Des avancées techniques et statistiques récentes permettent d’analyser et de comparer des multiples niveaux moléculaires et métaboliques simultanément et en profondeur. Nous allons appliquer ces méthodes pour mieux comprendre les changements métaboliques de la maladie d’Alzheimer. Lors de la première phase du projet, nous examinerons des données déjà existantes afin d’identifier des molécules et des altérations métaboliques. Ces données couvrent des aspects cliniques-neuropsychologiques et des analyses biologiques, à la fois dans le sang et dans le liquide céphalo-rachidien. Dans une deuxième étape, nous chercherons à confirmer ces résultats dans une nouvelle cohorte de patients qui seront recrutés dans 3 centres cliniques universitaires (à Zurich, Berne et Lausanne). Cette approche permettra de vérifier si les résultats sont identiques dans un contexte clinique plus large. Nous analyserons ensuite comment les molécules et processus identifiés sont en lien avec la progression de la maladie et si les molécules fortement associées à la maladie et aux manifestations cliniques peuvent être utilisées à des fins de diagnostic.

Contexte scientifique et social du projet de recherche : Le projet permettra d’améliorer notre compréhension des mécanismes pathologiques liés à la maladie d’Alzheimer et de leurs conséquences cliniques. Il offre la possibilité de découvrir des outils de diagnostic et de nouvelles pistes de traitements personnalisés.

Direct link to Lay Summary Last update: 19.11.2021

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
141179 Macrophage migration inhibitory factor and neuroinflammation in early Alzheimer’s Disease 01.03.2013 Project funding

Abstract

Besides amyloid pathology and tau-related neurodegeneration, multiple other molecular alterations and pathway dysregulations have been observed in Alzheimer’s disease (AD). Their inter-individual variations, complex interrelations, and relevance for clinical manifestation and disease progression remain poorly understood, however. Heterogeneity at both pathophysiological and clinical level complicates diagnosis, prognosis, treatment, and drug design and testing. Recently developed high throughput “omics” are unbiased data driven methods which allow addressing a wide spectrum of disease related changes at different endophenotype levels. Here, our main objectives are 1) to investigate in depth the systemic and CNS molecular AD endophenotypes by using integrative multi-omics analysis; 2) to relate the identified molecular and pathway alterations to core AD pathology, clinical manifestation, and disease progression and, 3) to derive novel multimodal blood-based biomarker signatures for individual diagnosis, differential diagnosis and prediction of disease progression. To this end, we will use a dataset from an existing thoroughly characterized, longitudinally followed up cohort, and acquire new data in subjects with normal cognition and with AD and non-AD cognitive impairment. Single-omics from paired CSF and peripheral blood samples including Proteomics, Metabolomics, Neuroinflammation, Methionine metabolism, Fatty acids, Lipidomics and Ionomics will be considered. Statistical approaches including machine learning and graph-based analysis will be applied to explore associations of molecular alterations with a) amyloid aggregation, tau pathology, neuronal injury, regional brain atrophy, and b) cognitive decline within single omics modalities. In parallel we will apply a data-driven integrative multi-omics factor analysis approach to address interrelations of multiple pathophysiological alterations across different omics levels. This will generate a latent factor representation of the dataset complexity to extract common axes of variance, and identify analytes associated with markers of core AD pathology or independently contributing to variance. Pathway enrichment will identify pathway alterations related to core AD pathology and/or, independently contributing to clinical severity, and disease progression over time. Blood sampling and targeted analysis at follow-up visits will be performed to relate dynamics of systemic alterations to clinical progression. To validate and extend the findings while addressing multiple possible confounders, we will acquire a new independent cohort from 3 Swiss university centers including subjects with AD, non-AD cognitive impairment, and controls; and perform targeted omics related to the identified mixed pathophysiological alterations. For additional validation, we will use clinical and omics data available from a large multi-cohort biomarker discovery project (EMIF consortium). Finally, blood-based biomarker combinations that best diagnose cerebral AD pathology and predict rapid cognitive decline will be determined in the first cohort and their performance will be verified in the independent multicenter cohort. Taking multiple clinical and endophenotype levels into account, this project will allow for the deep exploration of pathway alterations and improve our understanding of the mechanisms involved in cerebral AD pathology, associated systemic alterations, clinical manifestation, and progression of the disease. It has a high potential for biomarker discovery and translation to clinical application. We expect the results to lead to personalized medicine approaches for both diagnosis and intervention.
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