Proteomics

ADAPTED: Identifying new medicines to treat Alzheimer’s Disease through greater understanding of the APOE gene.

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The ADAPTED (Alzheimer’s Disease Apolipoprotein Pathology for Treatment Elucidation and Development)  project was a major new initiative to investigate an area of Alzheimer’s Disease (AD) research that has previously received little attention.

The project aimed to improve understanding of the function of the APOE gene. APOE is well known as a risk factor for developing the disease but precisely how this gene contributes to the risk of developing AD is not known. DC Biosciences was a project partner and its work with the consortium saw our scientists employing innovative quantitative proteomic technologies to explore these objectives.

ADAPTED brought together researchers from institutes and universities with those in the private sector, making use of a variety of cutting-edge biological analysis methods and calling on the field’s leading experts. Keiryn Bennett Ph.D. from DC Biosciences spent 2 years working on the project, supporting the research with her expertise in proteomics.

See the full list of consortium members.

It was hoped, in-depth study of the APOE gene would give scientists a clearer picture of its intricate composition, and provide the research community with a new generation of human cell-based tools to mimic and investigate the causes and progression of the disease.

The 4-year long study concluded in September 2020, leaving an extensive legacy of cells, data, and publications for the wider research community.

Cells

Three sets of isogenic iPSC lines developed by the ADAPTED APOE models team are available for researchers to purchase through the European Bank for Induced Pluripotent Stem Cells (EBiSC).

These lines have been developed by the reprogramming and editing of a single source of dermal fibroblasts to create individual lines with one of the APOE genotypes: APOE ε2/ε2, APOE ε3/ε3, APOE ε3/ε4, APOE ε4/ε4 or knock-out controls.

Data

The ADAPTED data team has 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 unraveling 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 after peer review.

Publications

To date, ADAPTED has published 7 peer-reviewed scientific papers, on various findings related to the study of APOE.

One paper shows how the PLCG2 enzyme is a potential target for therapeutic intervention in AD, and another that the proteins CDH6 and HAGH are significantly higher in AD patients, and could be used as new blood-based biomarkers for the detection of presymptomatic AD.

An interesting demonstration of the human blood-brain barrier was also carried out to study the effects of different APOE genotypes on barrier function and how potential therapies could be transported into the brain.

A common genetic signature shared by heart function and Alzheimer’s Disease has also been identified. This could be used to create preventative strategies by monitoring heart disease and screening for cognitive issues.

For details of these publications and others see the ADAPTED publications page.

Two more manuscripts are at the point of being submitted for peer review, and a further 16 manuscripts are in preparation.

The ADAPTED consortium has created a rich legacy of cells, data and publications for the wider Alzheimer’s disease research community for many years to come.

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