To cope with the pressing need for new therapies, researchers have been turning to iPSC-based models. Traditional animal models have offered some insights, but there is still a translational gap- after all, mice don’t get Alzheimer’s! Human iPSC-based models can be used to provide greater relevance for drug discovery, as researchers can use cells derived from AD patients to probe disease mechanisms and test potential therapies.
Patient-derived cells enable researchers to probe disease mechanisms related to specific mutations including those relating to familial AD (APP, PSEN1 and PSEN2) and, importantly, those associated with sporadic AD (sAD) representing ~95% of AD cases. The APOE4 allele has gained increasing interest as a major risk factor for sporadic AD (sAD), opening up a potential avenue for research and drug discovery4. But what has the research found, and how can we incorporate this into iPSC-based models?
The role of APOE4 in Alzheimer’s Disease
The APOE gene codes for the apolipoprotein E molecule that plays a key role in lipid transport, neuronal repair and remyelination4. There are three main isoforms, APOE2, APOE3 and APOE4, that have slightly different structural and functional properties.
Evidence from animal models and in vitro research has pointed to APOE4 as a major risk factor for AD, with a protective role for the APOE2 genotype and a neutral role for the APOE3 genotype4,5,6. Homozygous APOE4 (i.e, E4/E4) has been associated with the highest risk (around 15x) of developing Alzheimer’s Disease, leading researchers to investigate the value of APOE4 in advanced in vitro AD models.
This was taken a step further in a recent Nature Medicine paper from Fortea et al. looking at APOE4 homozygosity and its potential role as a genetically distinct form of Alzheimer’s Disease (AD)5.
The researchers performed post-mortem analysis from over 3,000 donors and discovered signs of AD in almost all of the APOE4 homozygous patient samples. Clinical studies of over 10,000 patients revealed higher levels of AD biomarkers in APOE4 homozygous patients compared to APOE3, and by age 65, almost all of the APOE4 homozygous patients had high levels of amyloid beta. The researchers have concluded that APOE4 homozygosity may represent a genetically distinct cause of AD, which may need “individualized prevention strategies, clinical trials and treatments”
While the specific conclusion has been disputed and the study has some notable drawbacks (for example, participants were mainly of European ancestry) it highlights the complexity of AD pathophysiology and the need to incorporate a diverse range of genotypes in advanced in vitro models.
Unlocking iPSC technology for APOE4 Alzheimer’s Disease models
At Axol Bioscience, we support researchers looking to unlock the benefits of iPSC technology for neurodegenerative disease research including Alzheimer’s Disease.
If you’d like to incorporate APOE4 into your in vitro projects, here are the key points you need to know:
- Our ax7111 iPSC line is derived from an 87-year-old donor who is APOE4 homozygous
- We have neural stem cells derived from this line (ax0111) available off-the-shelf for rapid maturation to end-point cells
- Previously, we have performed custom differentiation of our APOE4 homozygous line to astrocytes and microglia. If you’d like to discuss a similar project, we are happy to discuss.
- Alongside ax7111, we have healthy control lines for use in advanced in vitro AD models
Below you can find a summary of the main iPSC lines and donor information:
