September 9, 2015

expert reaction to evidence for human transmission of amyloid-Beta

Publishing in the journal Nature, a group of researchers has described their autopsy examination of eight individuals with CJD which was caused by treatment with “human cadaveric pituitary-derived growth hormone contaminated with prions” earlier in life. They report the presence of markers of Alzheimer’s disease in a number of cases and suggest that this may also be due to the treatment with contaminated hormone.

On dentistry and blood transfusions specifically:

Professor Nigel Hunt, Dean of the Faculty of Dental Surgery, said:

“This study alone does not provide any conclusive proof that Alzheimer’s disease can be transmitted from person to person. Dental practice carries no more risk than any invasive clinical procedure. This is new research in a field of relatively recent scientific enquiry that needs to be taken seriously with further research to inform any changes to all clinical and dental practice.

“In dentistry patients are protected from infection risks through the widespread use of single use instruments. All dental instruments that are reused are covered either by guidance from NICE or guidance about decontamination in primary care dental practices. The findings from today’s study must be considered by all relevant organisations to ensure current guidance is as robust as it needs to be.”

Dr Tara Spires-Jones, Reader and Chancellor’s Fellow, Centre for Cognitive and Neural Systems, University of Edinburgh, said:

“This study does not imply that Alzheimer’s could be transmitted via dental procedures. The study was based on 8 people NONE of whom had Alzheimer’s. Compare that to the thousands of people who have been studied finding no link of Alzheimer’s being transmissible. I can find zero reports in the scientific literature of this type of Alzheimer’s pathology being present in teeth roots so it is highly unlikely that there will be seeds present on dental instruments. This study is scientifically important as it suggests that if exposed to brain tissue from patients with Alzheimer’s pathology, there is a possibility of seeding that type of brain pathology in other people, but even this possibility will need to be confirmed in other studies. And this pathology alone is not Alzheimer’s disease, only one of the associated brain changes.”

Prof. Masud Husain, Professor of Neurology & Cognitive Sciences, University of Oxford said:

“There is no reason based on these findings to worry about catching Alzheimer’s disease from dental procedures.”

Dr Eric Karran, Director of Research at Alzheimer’s Research UK, said:

“While it will be important for further studies to explore any potential implications of today’s research, there is currently no evidence to suggest that the amyloid protein could be passed through dental surgery or blood transfusions.”

Prof. David Allsop, Professor of Neuroscience, University of Lancaster, said:

“There is no evidence that Alzheimer’s disease can be transmitted from one person to another, or through use of contaminated surgical instruments, and these results should be interpreted with a great deal of caution.”

Prof. Roger Morris, Professor of Molecular Neurobiology, King’s College London, said:

“Does this Nature paper, from the London labs of John Collinge and Sebastian Brandner, presage a new era in which Alzheimer’s disease changes from being an isolated disease of each individual as they age, to becoming infectious and able to attack everyone, young and old?

“No. This is a landmark paper in providing evidence, for the first time in man, of a mechanism for the propagation of Alzheimer’s disease that we already know exists from experimental studies in mice: the amyloid fibrils formed in the brains of Alzheimer’s patients, if injected into normal brain, infect the host brain.

“The conditions under which Alzheimer’s appears to have been infectiously transferred, as a contaminant of therapies designed to promote growth in children of small stature (human growth hormone) or to repair aspects of brain damage (dura matter grafts), between 1958-85, will never be repeated. The lethal neurodegenerative disease transferred in these patients was Creutzfeldt-Jakob Disease (CJD).   Around 450 patients have died from CJD transferred in these contaminated therapies world-wide.  Measures have now been put in place to prevent any further iatrogenic (meaning caused by the physician) transfer of CJD, and they will almost certainly contain Alzheimer’s.

“Arguably the most important point of this paper is to provide observational evidence in man, adding to the growing weight of experimental evidence in mice, that Alzheimer’s, the most common neurodegenerative disease, shares mechanistic features with CJD. Although CJD is very rare in man (accounting for one death per million of the population), it can be studied more precisely in experimental animals that can Alzheimer’s, enabling the initial causes of neurodegenerative disease to be dissected. This paper will further stimulate research into the common elements of these devastating neurodegenerative diseases, which should in time provide new insights and much needed opportunities for therapeutic development.”

Prof. David Allsop, Professor of Neuroscience, University of Lancaster, said:

“I can imagine that this might result in a lot of misleading headlines. What the paper shows is that some people treated with human growth hormone who subsequently went on to develop CJD also show evidence of β amyloid deposits, a key feature of Alzheimer’s disease, in their pituitary glands. What the paper does NOT demonstrate is whether these people would have gone on to develop Alzheimer’s disease had they lived long enough (they died of CJD) or that their pituitary β amyloid deposits were caused by contamination of growth hormone with a ‘rogue’ form of β amyloid. One possible (and indeed likely) explanation is that deposition of the ‘prion protein’ in CJD can result, in some cases, in the co-accumulation of β amyloid.

“It is very well known from other studies that one type of rogue protein (in this case the prion protein) can predispose to accumulation of another (in this case β amyloid). There is no evidence that Alzheimer’s disease can be transmitted from one person to another, or through use of contaminated surgical instruments, and these results should be interpreted with a great deal of caution.”

Prof. Masud Husain, Professor of Neurology & Cognitive Sciences,  University of Oxford said:

“While this is a beautiful piece of investigative medicine, we have to keep the findings in context. They concern a rare group of people who sadly developed CJD. They didn’t die of Alzheimer’s disease and the findings in their brains show only some of the features observed in Alzheimer patients. These results certainly do not provide sufficient evidence to believe Alzheimer’s disease is a transmissible illness. The authors argue that the prion (CJD) pathology and the amyloid (‘Alzheimer’) pathology are effectively independent. In other words, they suggest that the prion transmission did not trigger the deposition of amyloid. Stronger evidence would be required to accept such a proposal. Crucially, a previous analysis of a population of patients who developed CJD in this unfortunate way has not revealed a higher risk of developing Alzheimer’s disease.”

Dr Eric Karran, Director of Research at Alzheimer’s Research UK, said:

“Previous research has suggested that the amyloid protein may behave in a similar way to the prion protein responsible for CJD, but this study provides evidence that amyloid could also be passed between humans through contaminated brain tissue. While the findings sound concerning, it’s important to remember that human-derived hormone injections are no longer used and were replaced with synthetic forms since the link to CJD was discovered in the 1980s. It’s unusual for people of the ages studied in this research to have amyloid in the brain, but we don’t know whether they would have gone onto develop Alzheimer’s and there is currently no evidence that people who received human-derived growth hormone have a higher rate of the disease.

“The findings are from a very small number of people, but deserve further detailed investigation of those who received these transplants. The study highlights the potential for research into prion and CJD to provide important insights into diseases like Alzheimer’s too. It will also be important to investigate whether proteins linked to other neurodegenerative diseases, including other forms of dementia, could be transmitted in a similar way.

“Current measures in place to limit contamination with the prion protein and minimise CJD risk from hospital procedures are very rigorous and the risk of developing CJD from surgical contamination is extremely low. The biggest risk factor Alzheimer’s is age, along with genetic and lifestyle factors. If further research was to confirm a link between historical tissue contamination and Alzheimer’s, it would only likely be relevant to a tiny proportion of the total number of people affected.”

Dr Doug Brown, Director of Research at Alzheimer’s Society, said:

“While these findings are interesting and warrant further investigation, there are too many unknowns in this small, observational study of eight brains to draw any conclusions about whether Alzheimer’s disease can be transmitted this way.

“Notably, while seven of the eight brains studied had beta-amyloid deposits – a protein found in the brains of people with Alzheimer’s disease – the presence of this alone does not mean that they would have gone on to develop the disease.

“Injections of growth hormone taken from human brains were stopped in the 1980s. There remains absolutely no evidence that Alzheimer’s disease is contagious or can be transmitted from person to person via any current medical procedures.”

Prof. John Hardy, Professor of Neuroscience, UCL, said:

“Work largely from Germany over the last 5 years has shown that the amyloid pathology of Alzheimer’s disease could be transmitted from mouse to mouse on injection of amyloid.  In the 1980s Creuzfeldt-Jacob (prion) disease was transmitted to a small percentage (~4%) of individuals who were given human brain derived growth factor. They developed this presumably because the injections contained infectious prion protein.

“This study reported today shows that about half of those patients (that is about 2% of the original cohort) also, unexpectedly, had amyloid pathology in addition to their prion pathology suggesting, perhaps, that the amyloid pathology also infected the injected humans.  We do not know the clinical outcome of the vast majority of those who received the growth factor injections but they did not get prion disease.

“What does this mean?  With the previous mouse data, I think we can be relatively sure that it is possible to transmit amyloid pathology by the injection of human tissues which contain the amyloid of Alzheimer’s disease.  Does it have implications for (for example), blood transfusions: probably not, but this definitely deserves systematic epidemiological investigation.  Does it suggest Alzheimer’s disease is infectious through contact?  Almost certainly not.”

Dr Liz Coulthard, Consultant Senior Lecturer in Dementia Neurology, University of Bristol, said:

“This is a very detailed description of pathological changes in the brain of people who received cadaveric human growth hormone between 1959 and 1985 and subsequently developed the prion disease CJD. In addition to the brain changes expected in CJD, 7 of the 8 patients examined also had evidence of amyloid deposition, one of the pathological changes found in Alzheimer’s disease. The Alzheimer’s and CJD proteins were in sufficiently distinct parts of the brain that the authors propose both amyloid and prion protein had been transmitted through growth hormone injections. Based on this work, the authors suggested that perhaps Alzheimer’s disease could be transmitted through medical equipment because pathological proteins are resistant to standard sterilisation procedures. However, Alzheimer’s disease itself does not seem to be more common in people who have received cadaveric growth hormone treatment arguing against significant risk from human-to-human transmission. Despite the fact that previous data make it very unlikely that human-to-human transmission causes Alzheimer’s disease, further work is required to tease apart whether even a small proportion of Alzheimer’s cases might have been transmitted. In the meantime, there is limited evidence on which to assess the risk from invasive surgical procedures.”

Mr Richard Kerr, Consultant Neurosurgeon, Royal College of Surgeons Council Member and Society of British Neurological Surgeons President, said:

“This is new information in a field of highly complex scientific enquiry that needs to be taken seriously. With such a small study however, further research is needed so we can learn more about transfer and whether existing decontamination procedures are effective. This of course will inform any clinical decisions that need to be taken to manage and reduce even the smallest risk to patients.

“At the moment there is already guidance from NIHCE on the use of instruments and endoscopes that might be involved in the transmission of Creutzfeldt-Jacob Disease (CJD / vCJD). These guidelines are currently being updated by NIHCE for publication later this year. The findings from today’s study must be considered by all relevant organisations and addressed in the same way.”

Dr Tara Spires-Jones, Reader and Chancellor’s Fellow, Centre for Cognitive and Neural Systems, University of Edinburgh, said:

“While this is a very interesting scientific study, it is important to note that this is not evidence that Alzheimer’s disease can be transmitted from one person to another – rather it suggests, based on 4 people,  that one of the types of brain pathology associated with Alzheimer’s may be seeded by receiving injections of human brain material. Brains from eight people who contracted prion disease (iCJD) from human growth hormone injections were studied after they died, and four of those were found to have substantial amyloid beta pathology, which is found in the brains of people with Alzheimer’s disease. It is important to note that the presence of these amyloid beta deposits is not the same thing as having Alzheimer’s disease. Amyloid beta pathology is only one of the markers of Alzheimer’s. To have Alzheimer’s disease, a person must have symptoms of dementia along with amyloid beta pathology, tau pathology, and brain cell death.

“While it is possible that these people may have gone on to develop the other markers of Alzheimer’s with time, this is by no means certain. Many people develop amyloid beta pathology in older age without ever developing Alzheimer’s. Furthermore, this observational study in post-mortem brain cannot prove that the amyloid deposits were caused by the injections (although several control comparisons suggest it is possible).  Finally, it appears from the extended data figure 2e that many people with prion disease who had not received injections of growth hormone also develop amyloid beta pathology.  This means that amyloid beta pathology could develop in patients with prion disease in general – without being transmitted from another person.

“This is an interesting study in a small sample of human patients that raises the possibility that Alzheimer-like pathology can be initiated by injecting people with human brain derived products (such as human growth hormone injections).  This process of injecting people with human growth hormone was stopped around 20 years ago, and as correctly pointed out by the scientists covering this study in the news and views piece in Nature, ‘So far, there is no indication that Alzheimer’s disease can be transmitted between people under ordinary circumstances.’”

Prof. Simon Lovestone, Professor of Translational Neuroscience, University of Oxford, said:

“In the past growth hormone was extracted from the pituitary gland from deceased donors. Pools of these glands were made from many people and so recipients were exposed, by injection, to brain material from large numbers of people, many of whom would have been elderly. This process was stopped in 1985 when it was realised that prion diseases (CJD) could be acquired through this therapy. This paper examines the brains of a very small number of middle aged people half of whom were found to have amyloid deposits in their brains raising the question as to whether Alzheimer’s disease can be acquired through this route.

“Although a very interesting paper, I don’t think we need to worry excessively. For two main reasons. First, the study shows that these middle aged people had only evidence of amyloid deposits in their brains. Alzheimer’s disease is a disorder with two features – amyloid deposits called plaques and tau deposits called tangles. There were no tau deposits or tangles in these cases and as it is these lesions or abnormalities that are actually thought to cause the damage to brain cells and hence the cognitive impairment of dementia, then their absence is important and reassuring. Second, this form of treatment stopped 20 years ago and there is no evidence from this paper or any other work I am aware of that any other form of treatment would result in exposure to amyloid. As these authors say “there is no suggestion that Alzheimer’s disease is a contagious disease and no supportive evidence from epidemiological studies that Alzheimer’s disease is transmissible”. I agree with this and as the authors note, other studies have examined whether there is an increased risk of dementia in people who have had blood transfusion, for example, and there isn’t.

“However, the findings that are reported here are important to those of us researching the causes and seeking a treatment for Alzheimer’s. For example one of the most important questions in the field is whether amyloid in the brain results in the series of biochemical and cellular changes that result in tangles made of tau and hence brain cell damage and dementia. In animals it seems it isn’t simple and amyloid in the brain does not result in tangles and dementia in mice for example. Previously some studies have suggested that the same might happen in people – amyloid deposits in the brain without tangles and dementia. This study finds the same thing. The authors wonder if these people had lived longer they might have developed tangles and dementia. This is possible of course but we don’t know and as in animal studies and in some other human studies it might be that there are other risk and protective factors that interact with amyloid. Following up more people who had growth hormone from cadavers more than 20 years ago might help us to address this critically important question.

“For the time being though, although interesting to researchers, this paper should make us cautious but not overly concerned.”

‘Evidence for human transmission of amyloid-beta pathology and cerebral amyloid angiopathy’ by Jaunmuktane et al. published in Nature on Wednesday 9^th September. 

Declared interests

Profs Husain, Hardy and Karran – None to declare

All others – None received