March 28, 2024

expert reaction to study looking at a mouse model of a stem cell transplant that reports transmission of a rare familial form of Alzheimer’s disease

A study published in Stem Cell Reports looks at a stem cell transplant in mice and transmission of a familial form of Alzheimer’s disease.

Dr Sheona Scales, Director of Research at Alzheimer’s Research UK says:

“There is currently no evidence that people who have stem cell or other tissue transplants have an increased risk of Alzheimer’s disease. Nor can Alzheimer’s be caught from contact with someone with the disease, or from regular medical treatments.

“This new research shows that stem cells from mice bred to carry a known Alzheimer’s risk gene can cause Alzheimer’s-like changes when transplanted into other mice who lack this faulty gene.

“Much more research is needed to understand whether this process is ever likely to occur in people. It is important to note that these experiments were done in mice engineered to carry a rare genetic mutation, which accounts for an extremely small number of Alzheimer’s cases in people. And while animal research can give valuable clues into how the diseases that cause dementia start and develop, there are key biological differences between mice and people. It is not clear that this mechanism is relevant outside of a laboratory experiment.

“But studies like this are deepening our understanding of Alzheimer’s disease, and this will open up new ways of treating, preventing, and diagnosing dementia in the future”.

Prof Tara Spires-Jones, President of the British Neuroscience Association and Group Leader in the UK Dementia Research Institute at the University of Edinburgh said:

“This study transplanting bone marrow stem cells from mice engineered to carry a familial Alzheimer’s disease mutation into healthy mice was run in a single mouse model with very small numbers of mice per group (one animal per group shown in figure 1, 4-18 mice per group in other figures). The conclusion in the press release that “the recipients developed Alzheimer’s disease” is not supported by the data.  The recipient mice did not develop Alzheimer’s disease, they had small amounts of pathology and memory deficits in small groups of animals. They did not have neurodegeneration or tau pathology which occur in Alzheimer’s disease. While other data in the field do support the idea that amyloid pathology “seeds” can induce clumping in healthy brain, there has never been conclusive evidence that this leads to dementia. Further, familial Alzheimer’s disease mutations such as the one used in this study are exceedingly rare, so these results should not cause concern to people who need bone marrow transplants.”

Prof Paul Morgan, UK Dementia Research Institute Cardiff, Cardiff University, said:

“This article reports some interesting data on transmission of Alzheimer-like pathology by bone marrow transplantation in mice and proceeds to make the gargantuan leap to propose that tissue, organ and cell transplantation, and even blood transfusion, carry a risk of transferring Alzheimer’s disease and other neuropathologies in man.  

“In the model, bone marrow from donor mice carrying a mutant human APP gene associated with a very rare and severe familial form of Alzheimer’s disease (only found in two families in Sweden!) was transferred into recipient mice, unmodified or knockout for the mouse APP gene. The recipient mice were subjected to whole body radiation prior to the transfer, ablating their immune systems and damaging the blood-brain barrier; crucial to allow the transplanted cells to survive and likely permitting their access to the brain.  In the subsequent months the recipient mice developed brain pathologies and behavioural changes resembling those in the donor strain, suggesting that the transferred bone marrow cells had delivered the mutant gene in a form that could drive the associated brain disease.

“The findings are scientifically intriguing in that they show, in this very specific experimental situation, that bone marrow cells are sufficient to transfer the gene and the disease.  Relevance to human organ and cell transplant is limited. To their credit, the authors do clearly state the limitations of their study in the discussion; however, this is not helped by some broad statements elsewhere in the text suggesting relevance to human transplantation and transfusion, which should not be used to justify hyped up headlines.”

Prof Bart De Strooper, Group Leader at the UK DRI at UCL, said: 

“The fact that bone marrow cells could be sufficient to induce amyloid pathology in the brain is surprising, as current evidence suggests that the amyloid accumulation in the brain of people with Alzheimer’s originates from neurons and supporting glial cells. This paper could be of great interest, however, the data supporting the claims are too limited to make final conclusions. There are a number of issues with the analysis, for instance the quantitative assessment of the amyloid beta levels in the brains of the transplanted animals is missing. In addition, there are other results which are unclear or not of good enough quality to be convincing, namely figures 4A-C. There is not sufficient evidence here to suggest that anyone receiving a bone marrow transplant is at risk of developing Alzheimer’s disease as a result of the procedure, and nobody should forego a transplant for this reason.”

Prof David Curtis, Honorary Professor, UCL Genetics Institute, UCL, said:

“This study demonstrates that injecting stem cells containing DNA coding for a very rare familial form of Alzheimer’s disease can lead to the development of features of the disease in mice. It is already well known that such stem cells will travel to the brain and develop into cells called glial cells, which surround the neurons in the brain. Thus, this study seems to suggest that the neurons themselves do not have to produce the abnormal amyloid protein which results in signs of Alzheimer’s disease. However, it does not prove that the disease is due to production of the protein outside the brain, because glial cells are very much within the brain.

“The study suggests that theoretically there could be a risk of acquiring Alzheimer’s disease if one received a stem cell transplant from somebody carrying the severe, familial form of the disease. However this form is extremely rare so in practice the risk seems low and there are many safeguards around stem cell transplantation. I do not see that the risks extend to other areas such as organ transplantation or blood transfusion because these procedures do not involve large numbers of stem cells which can go on to form glial cells.”

‘Conclusive demonstration of iatrogenic Alzheimer’s disease transmission in a model of stem cell transplantation’ by Chaahat S.B. Singh et al. was published in Stem Cell Reports at 15:00 UK time on Thursday 28^th March.

DOI: https://doi.org/10.1016/j.stemcr.2024.02.012

Declared interests

Prof Tara Spires-Jones: I have no conflicts with this study.

Prof Paul Morgan: No conflicts

Prof Bart De Strooper: I have no direct conflicts of interest with the current manuscript. I am however consultant of several pharmaceutical companies working on Alzheimer’s Disease.

Prof David Curtis: I have no conflict of interest

For all other experts, no reply to our request for DOIs was received.