The past decade has seen major progress in unravelling the genes, protein and metabolic pathways implicated in neurodegenerative disorders (NDD) including Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS, also known as motor neuron disease, MND). The gap in our knowledge is how these cross-omics features translate into onset and progression of disease. AD, PD, and ALS are heterogeneous disorders. The interplay between genes, proteins, metabolites and clinical, pathological, radiological, and epidemiological characteristics is far from understood. Dissecting the cross-omics features in NDD to define clinical and molecular subgroups allow more precise treatment/prevention and will empower future trials. We plan to perform multi-omics integration in multiple deeply phenotype cohorts (e.g. OPTIMA, OPDC, ALS cohorts of oxford) and validate those findings in the UKB population-based setting. Specific aims of the project are:
-Validating the discoveries of cross-omics, mathematical modelling and clinical markers identified in the OPTIMA, OPDC, ALS cohorts
-Identifying predictive biomarkers of progression of NDD in clinically relevant endophenotypes.
-Discovery of biomarkers of NDD target engagement that allow patient stratification, and discovery of parameters for mathematical models.
Cellular and animal models have led to major advances in our understanding of the neurobiology of NDD. These advances have been paralleled by unprecedented investments (public – private) in human research of NDD using -omics, CSF /plasma biomarkers and imaging (e.g., UKB, ADNI, AMPAD, AMPPD). However, there remains a large and fundamental bi-directional knowledge gap:
-From bedside to bench connecting individual patients to biological mechanisms, so that their underlying pathology can be targeted with specificity and sensitivity.
-From bench to bedside linking neurobiology to the different phenotypic presentations in patients with AD.
