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Alzheimers Disease Apolipoprotein Pathology for Treatment Elucidation and Development - Sofia ref.: 115975

Periodic Reporting for period 3 - ADAPTED (Alzheimers Disease Apolipoprotein Pathology for Treatment Elucidation and Development - Sofia ref.: 115975)

Reporting period: 2018-10-01 to 2020-09-30

ADAPTED has a focussed set of objectives aimed at;
1. Clarifying the role of APOE as a risk factor in the development of AD
2. Identifying promising entry points (targets) for the treatment of AD
3. Generate and validate selected high value APOE-related model systems
4. Uncover the basic scientific evidence required to progress the development of a stratified approach

The principles used to achieve this include;
Generation and characterization of novel high quality gene-edited and patient derived iPSC-derived models as well as the use of available patient-derived tissue to identify APOE genotype and disease pathways and processes in an unbiased manner as well as directed approaches beyond APOE’s interaction with Aβ e.g. synaptic and mitochondrial function and neuroinflammation.
Elucidate the time course of APOE-ɛ4 effects on neurodegeneration and thus identify promising points of intervention for novel treatment strategies by studying cholesterol influx/efflux impairment in macrophages with different APOE genotypes and from large available Mild Cognitive Impairment (MCI) datasets evaluate the role of factors identified in MCI to AD phenoconversion.
Advance understanding of both cell-autonomous and non cell-autonomous phenotypes by differentiating iPS cells to astrocytes, neurons, macrophages and endothelial cells, and studying them in a physiological context in multi-well based solutions and using the Organ-on-a-chip platform.
Resolve existing ‘toxic gain of function’ vs. ‘loss of function’ hypotheses and generate new, mechanistic hypotheses for APOE-ɛ4’s role in the development of AD.
Generate new knowledge of how APOE-ɛ4 interacts with other AD risk and genetic factors, including protective effects of APOE-ε2, influencing development of AD by integrating genomic, transcriptomic, metabolomics, proteomic and lipidomic data.
Identify early biomarkers of cognitive decline and MCI conversion to AD and prospective new targets for therapeutic interventions by integrative analysis of ADAPTED and publicly available data.
Provide evidence for biochemical markers in APOE-ɛ4 carriers that will convert to AD, or will develop a more aggressive phenotype, to inform decisions of when and how to intervene with treatments based on a systematic specificity analysis.
• Four fully characterised sets of isogenic iPSC lines carrying one of the following APOE genotypes: APOE-Ɛ2/Ɛ2, APOE-Ɛ3/Ɛ3, APOE-Ɛ4/Ɛ4, APOE-Ɛ3/Ɛ4, and APOE-KO have been developed. These cells are available to the scientific community, distributed by the ECACC (https://www.phe-culturecollections.org.uk).
• Existing CSF and blood samples from MCI subjects have been made available to the consortium, and new samples have been collected. CSF samples have been measured using state-of-the-art analytical techniques, focusing on metabolites involved in oxidative and nitrosative stress, as well as inflammation.
• A demonstration of a human blood-brain barrier on-a-chip model. This can be used, for example, to study the effects of different APOE genotypes on barrier function, or how potential therapies are transported into the brain.
• Using existing multi-omics data of EMC, UKK and Janssen, 12 metabolites circulating in blood (11 HDL sub-fractions and the fatty acid DHA) were found to be associated with improved cognitive function and 3 circulating metabolites (glycoprotein acetyls, glutamine and ornithine) with cognitive impairment. Stratified by APOE, we found that in those carrying the APOE*3 and the APOE*4 genotype, the metabolites determine conversion to AD. Findings were validated by external partners.
• We showed that a rare coding variant in the PLCG2 gene slows Alzheimer's disease progression and maintains cognitive function- apparently counteracting the deleterious effect of the APOE ε4 allele. This highlights the PLCG2 enzyme as a potential target for therapeutic intervention in AD.
• Using known AD susceptibility genes, different cognitive composites have been tested to define the best way to operationalize cognitive decline across longitudinal MCI cohorts. This analysis showed that when analysing several heterogeneous cohorts of MCI as in ADAPTED, MMSE has to be considered the most efficient neuropsychological discriminant factor for progression to dementia and rate of cognitive decline. Importantly, this analysis also revealed that a composite assessing memory and executive function detects the effect of ApoE4 more powerfully than the MMSE which assesses additional cognitive domains. This finding suggests that genetic risk factors for AD may exert their effect on specific neuronal networks underlying particular cognitive functions.
• Metabolite analysis revealed that AD patients carrying at least one APOE-ε4 allele showed a dysregulation in omega-3 and omega-6 fatty acid pathways. This dysregulation is not observed in healthy controls stratified similarly to AD patients. These findings are corroborated by Mendelian Randomization, suggesting that the dysregulation is rather a consequence and thus a biomarkers of the disease process rather than a causal effect.
• Lysophosphatidic acids (LPAs) are bioactive signaling phospholipids that have been implicated in Alzheimer’s disease (AD). We show that LPAs may contribute to early AD pathogenesis, and that APOE may influence the association between LPAs and Aβ-42
• Data from many publicly available datasets have been curated and integrated into the ADAPTED TranSMART database and is available for APOE stratified questioning. Three-stage integrative analysis has been carried out and has identified specific immunological signatures for APOE genotypes contributing to the susceptibility to Alzheimer’s disease.
• The database with publicly available datasets has been supplemented with the extensive omics (transcriptomics, metabolomics and proteomics) analysis performed throughout the consortium on human or humanized samples. This data will become available to the broader scientific community following their reporting in scientific journals.
The extensive QC of the iPSC lines has provided us new insights into required standards for gene-editing of iPSCs. More genetic variations are identified that would have been with state-of-the-art technology at the start of the project. The proposal to have four independently gene-edited iPSC sets comprising 5 genotypes each appeared conservative at the start of the project. The data which will be generated with the generated cells will shed more light on robustness of phenotypes.
We have carried out an integrative analysis aimed at combining information derived from publicly available multi-omics studies on Alzheimer’s disease with ADAPTED isogenic iPSCs towards the major goal of unravelling the role of APOE in the development of Alzheimer’s. This study integrates genome-wide association study (GWAS) data from 39,186 human genomes, 2,338 transcriptomes, and 2,365 proteomes from AD cases and controls, as well as transcriptomics from iPSC derived neurons, macrophages and microglia carrying the diverse APOE haplotypes mentioned above. These data will be made available for the use of the scientific community through European repositories after our findings have been published in open peer-reviewed journals.
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