ADAPTED aims to improve understanding of the function of the APOE gene and the role it may play in the development of Alzheimer's Disease (AD). This has the potential to establish a completely new list of prospective drug targets and, therefore, future medicines with which to treat the disease. This also could lead to improvements in the way those likely to suffer from the disease are identified, by improving the tests used for early diagnosis.
Apolipoprotein E (APOE) is a protein involved in the transport of cholesterol in the bloodstream. There are at least three different alleles of APOE known as ε2, ε3 and ε4. Carrying the APOE ε4 gene is the most prominent risk factor for sporadic, late-onset AD which comprises over 95% of AD cases. At least one copy of the APOE ε4 gene is found in approximately 60% of AD cases, with one ε4 allele conferring a threefold increased risk and two ε4 alleles conferring a twelvefold increased risk of developing the disease. Conversely, APOE ε2 protects against the disease. APOE ε4 carriers also have an earlier disease age of onset and the disease progresses faster.
While APOE ε4 has been clearly established as the most prominent AD risk factor, there has been comparatively little research into precisely how APOE may cause AD.
The project is split into five main areas of activity:
ADAPTED will establish new highly relevant human cell models to enable the systematic investigation of APOE biology.
This will be done by cell reprogramming and genome editing of cells from Alzheimer's disease patients and healthy controls to create a set of stem cell lines which differ only in their APOE genotype. These can then be differentiated into relevant cell types and co-cultures of these cells in 2D and 3D systems as well as an organ-on-a-chip model will be evaluated. The cells will also be differentiated into macrophages to develop a cellular system to validate major APOE-associated phenotypes identified in AD patient-derived macrophages.
These cells will be used within ADAPTED and will also be made available to the wider AD research community for future research.
APOE and neurodegeneration
The role APOE may play in causing the neurodegeneration seen in AD patients will be investigated using blood and cerebrospinal fluid (CSF) from AD patients and controls and also using the cell models described (see ‘APOE models’). We will perform a comprehensive –omics analysis to clarify the evidence for a toxic gain of function or loss of function of the different APOE genotypes and gain novel insights into the protective effects of the APOE-ε2 variant.
This will be complemented by high content imaging and investigating receptor signalling and electrophysiology to explore differences in neuronal networks across the APOE genotypes.
The aim of this work is to improve understanding of APOE interactions with other Alzheimer’s disease risk factors.
Mild cognitive impairment (MCI) is a slight but noticeable decline in a person’s cognitive abilities (e.g. memory or thinking skills). People with MCI are at increased risk of developing Alzheimer’s disease. We will investigate differences in the blood and cerebrospinal fluid of patients with MCI who go on to develop Alzheimer’s disease and compare this with samples from patients with MCI who do not develop Alzheimer’s disease and, in particular, we will explore how the different versions of the APOE gene (described above) may play a role in the progression of MCI to Alzheimer’s disease.
Key results from these investigations will be confirmed using animal models and post-mortem samples and may lead to the development of new tests better able to identify those at risk of developing Alzheimer’s disease.
APOE and Alzheimer's disease risk factors
ADAPTED Data management and sharing
The data generated by the ADAPTED project will be integrated with databases that are already available in public repositories and with the project partners. A data platform will be set up for secure data storage and handling and analyses of the data will be carried out as needed.
The project results and associated tools will be made publicly available to aid and encourage current and future research in Alzheimer’s disease.
ADAPTED Collaborations and sustainability
The management and communications systems within ADAPTED will be optimised to ensure the most efficient use of the project resources. ADAPTED will also reach out to other relevant research projects and initiatives to avoid duplication of effort and to maximise the scientific advances possible during the course of the project. Steps will be put in place to ensure the data generated by the project will be available to all Alzheimer’s disease researchers to use after the project finishes.