IPMAR: major new cellular model platform launched to transform understanding of risk factors for Alzheimer’s disease

Of the 50 million people living with dementia worldwide, Alzheimer’s disease is the most common cause. The risk of developing the late-onset form of the condition is estimated to be 60-80% genetic, and therefore greater understanding of this risk will help determine the causes of disease and a path to much-needed treatments.

Individuals with the familial, inherited form of Alzheimer’s disease have mutations in key genes that sadly guarantee the development of the condition. These mutations have been used for decades to create both cellular and animal models that mimic aspects of the human condition and help scientists learn more about Alzheimer’s.

However, in the majority of cases, the risk of developing the disease is likely to be a combination of the small effects from thousands of our genes, along with environmental factors such as lack of exercise. So scientists have more recently been analysing huge genetic datasets to determine polygenic risk scores (PRS), which are a calculation of an individual’s overall risk for developing Alzheimer’s disease.

Researchers from the UK DRI at Cardiff are leaders in this field and have produced the most robust calculations for PRS, with the ability to predict Alzheimer’s disease risk with 78-84% accuracy in the general population. The genetic work carried out by the team also points to the involvement of several biological pathways, suggesting multiple components combine to trigger disease.

The UK DRI at Cardiff is an internationally-recognised centre for Alzheimer’s genetics, and with Prof Williams as a co-leader of the International Genomics of Alzheimer’s Project (IGAP), they have collected together the largest group of research data around diagnosed Alzheimer’s cases in the UK, and healthy individuals for comparison - comprising 3,505 and 2,421 separate cases respectively.

The team plan to harness this resource, which includes clinical, genomic, longitudinal data and extensive biological samples (cell lines, plasma, serum, RNA, DNA, urine) taken over the past 20 years, to create and validate up to 60 human-derived iPSC lines for generating models with high and low polygenic risk for Alzheimer’s.

Furthermore, studies from Cardiff and elsewhere have shown that over 50% of genetic risk variants for Alzheimer’s can be found in immune cells found in the brain: microglia. The team therefore plan to change or ‘differentiate’ 44 of these new IPSC lines into microglia-like cells for more specific testing and analysis of risk variants in this cell type.

IPMAR Lead, Prof Julie Williams, said:

“These human iPS cells provide a novel means to model the most common form of Alzheimer’s disease which occurs after the age of 65. The polygenic score can capture the true complexity of this disease reflecting the combination of multiple genetic risk factors and allowing the research community to test for disease relevant changes in different environments, at different stages of disease development and test drugs which could reverse these effects.”