New stem cell bank enables global Alzheimer’s research
A groundbreaking stem cell repository has been established using blood samples from over 100 individuals selected for their extreme genetic risk profiles for Alzheimer’s disease. The IPMAR resource will enable researchers worldwide to study how genetic variants contribute to the neurodegenerative condition in laboratory models.
Researchers at the UK Dementia Research Institute at Cardiff University have created the first large-scale stem cell bank specifically designed to capture the extremes of Alzheimer’s disease (AD) polygenic risk. The iPSC Platform to Model Alzheimer’s disease Risk (IPMAR) resource comprises induced pluripotent stem cell (iPSC) lines from 109 donors carefully selected based on their polygenic risk scores (PRS).
The work, published in Stem Cell Reports on 3 July 2025, represents a significant advancement in AD research methodology. Unlike previous studies that have used iPSC models with individual protein-coding mutations from familial AD cases, this resource captures the complex genetic architecture underlying common forms of the disease.
Polygenic risk approach transforms disease modelling
The research team selected donors from a large UK cohort of over 6,000 research-diagnosed early-onset and late-onset AD cases, along with elderly cognitively healthy controls. “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,” the researchers report in their study.
The collection includes 63 iPSC lines from patients with common AD exhibiting high global PRS, comprising 34 from late-onset AD patients and 29 from early-onset AD patients. Additionally, 27 lines were derived from age-matched healthy controls with low global PRS. A further 19 lines were selected specifically for complement pathway-specific genetic risk.
Blood cells from these carefully selected individuals were genetically reprogrammed into iPSCs, which are immature cells capable of generating all cell types in the body. This approach allows researchers to study how genetic risk variants impact brain cell health and function in controlled laboratory conditions.
Bridging the gap between genetics and cellular dysfunction
Current AD research faces significant limitations when using mouse models or familial AD mutations, which may not accurately represent the polygenic nature of common AD. “Most AD research uses iPSC models with individual protein-coding mutations, from familial or common AD-associated risk genes,” the authors note. “While these studies allow us to develop our understanding of the pathways involved in AD pathogenesis, single-gene mutation models do not represent the polygenic diversity seen in common AD individuals and hence do not capture the complexity of disease.”
The IPMAR resource addresses this critical gap by providing researchers with cellular models that reflect the true genetic diversity underlying common AD. Each iPSC line retains the unique genetic makeup of its donor, including all the risk variants that contribute to their overall disease susceptibility.
High-accuracy genetic risk prediction
The polygenic risk scores used to select donors can predict an individual’s likelihood of developing AD with 84% accuracy. These scores aggregate information from more than 70 common and rare genetic variants identified through genome-wide association studies, beyond the well-established APOE ε4 risk allele.
The researchers emphasise that PRS analysis provides valuable insights into the genetic component of Alzheimer’s disease. “By assessing an individual’s genetic profile and summing up the effects of these variants, a PRS value provides a personalised estimate of an individual’s likelihood of developing AD,” they explain.
Enabling personalised medicine approaches
The IPMAR resource opens new possibilities for personalised medicine in AD research and treatment development. By providing access to iPSC lines representing different genetic risk profiles, researchers can investigate how various combinations of risk variants affect cellular function and drug responses.
“Following differentiation of these iPSC into AD-relevant cell types, researchers will be able to determine how high PRS AD lines differ phenotypically from low PRS control lines,” the authors suggest. This could help identify cellular phenotypes that either contribute to or protect against AD development.
The resource also includes comprehensive clinical, longitudinal, and genetic datasets associated with each iPSC line, providing researchers with rich contextual information for their studies.
Global accessibility and future directions
The IPMAR iPSC lines will be made available to researchers worldwide through collaboration or from established cell and data repositories including the European Bank for iPSC (EBiSC) and Dementia Platforms UK (DPUK). This global accessibility ensures the resource can facilitate international collaborative research efforts.
The researchers acknowledge certain limitations, including the restriction to White Caucasian subjects from the UK, which may limit the generalisability of findings to other populations. Future expansions of the resource are planned to include iPSC lines with high endocytic pathway-specific risk.
The establishment of IPMAR represents a paradigm shift towards more representative disease modelling in AD research. “The IPMAR resource has the potential to revolutionise both AD modelling and drug screening,” the authors conclude, highlighting its potential to accelerate the development of new therapeutic approaches for this devastating neurodegenerative condition.
Reference
Maguire, E., Winston, J., Ellwood, S. H., et. al. (2025). Modeling common Alzheimer’s disease with high and low polygenic risk in human iPSC: A large-scale research resource. Stem Cell Reports, 20, 102570. https://doi.org/10.1016/j.stemcr.2025.102570
