First large-scale stem cell bank created to investigate Alzheimer’s genetic risk factors

Alzheimer's disease (AD) is a common, debilitating neurodegenerative disease affecting about 10 percent of people over the age of 65 and one third of people aged 85 and above. Besides environmental factors, the genes have a strong influence on whether or not a person develops AD during their lifetime. Through genome sequencing of DNA from large groups of healthy people and people with AD, some naturally occurring small changes in the DNA, known as genetic variants, were found to be more frequent in AD patients than in healthy people. As more and more of these AD-associated genetic "risk" variants are discovered, it is now possible to calculate a person's individual polygenic risk score (PRS), meaning the likelihood of the person to develop AD, with high accuracy. Despite this progress, it is still largely unknown how genetic risk variants, or combinations thereof, cause AD in individual patients and more specifically, how risk variants impact the health and function of brain cells.

To address this, researchers in the UK Dementia Research Institute at Cardiff University, UK, have now generated the first large-scale stem cell bank from over 100 individuals selected for extremes of AD PRS, which had previously been determined by genome sequencing. The results of the work are published today in Stem Cell Reports. About two thirds of the donors had been diagnosed with AD and had a relatively high PRS while one third were cognitively healthy, age-matched individuals with a low PRS. Blood cells from these individuals were genetically engineered to turn them into induced pluripotent stem cells (iPSCs), which are immature cells capable of generating all cell types of the body. The new "iPSC Platform to Model Alzheimer's disease Risk" (IPMAR) resource will be made available to researchers worldwide to facilitate studies on the impact of risk variants in iPSC-based cellular models of AD in the lab. Ultimately, the resource can be used to increase our understanding of genetic risk factors linked to AD, and may inform the design of new, individualized treatments or prevention strategies.