Researchers headed by a team at University College London (UCL) have uncovered five cases of Alzheimer’s disease (AD) that they believe may have resulted from a type of medical treatment the individuals received decades earlier.
Alzheimer’s disease, which is characterized by the buildup of abnormally folded amyloid-beta (Aβ) protein in the brain, is usually a sporadic condition of late adult life, or more rarely may occur due to inheritance of a faulty gene. The newly reported study provides the first evidence of Alzheimer’s disease in living people that appears to have been medically acquired (iatrogenic), due to transmission of the amyloid-beta protein when they were treated as children using cadaver-sourced human pituitary-derived growth hormone (c-hGH), an approach that is now banned.
Research lead John Collinge, MD, director of the UCL Institute of Prion Diseases and a consultant neurologist at UCL Hospital, stressed, “The patients we have described were given a specific and long-discontinued medical treatment which involved injecting patients with material now known to have been contaminated with disease-related proteins … There is no suggestion whatsoever that Alzheimer’s disease can be transmitted between individuals during activities of daily life or routine medical care.”
Collinge is senior author of the team’s published paper in Nature Medicine, titled “Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone.” In their report the researchers further noted, “It is important to emphasize that the cases described here developed symptoms after repeated exposure to contaminated c-hGH, over a period of years, and that treatment with c-hGH was discontinued many years ago … Although iatrogenic AD may be rare, and there is no suggestion that Aβ can be transmitted between individuals in activities of daily life, its recognition emphasizes the need to review measures to prevent accidental transmissions via other medical and surgical procedures.”
c-hCG treatment was used in at least 1,848 people in the U.K. between 1959 and 1985, as a treatment for various causes of short stature. However, this form of therapy was withdrawn in 1985 after recognition that some c-hGH batches were contaminated with prions (infectious proteins) that had caused Creutzfeldt-Jakob disease (CJD) in some of the treatment recipients. “Worldwide, over 200 cases of iatrogenic CJD have occurred as a consequence of childhood treatment with c-hGH, with 80 cases recorded in the United Kingdom,” the authors wrote. c-hGH was then replaced with synthetic growth hormone that did not carry the risk of transmitting CJD.
The researchers had previously reported that some patients who developed CJD following c-hGH treatment also had prematurely developed deposits of the Aβ protein in their brains. “We first reported human-to-human transmission of Aβ pathology in people who had received c-hGH in childhood and died of iatrogenic CJD,” they wrote. The scientists went on to show that archived samples of c-hGH were contaminated with amyloid-beta protein and, despite having been stored for decades, transmitted amyloid-beta pathology to laboratory mice when it was injected. “… we later demonstrated that some of the archived batches of c-hGH used to treat these people contained measurable quantities of Aβ (and tau) and that this historical material still contained Aβ seeding activity able to transmit pathology to mice.” These experiments, they said, “ provided clear evidence that iatrogenic Aβ transmission had occurred in people treated with c-hGH.” Multiple postmortem reports of iatrogenic Aβ transmission caused by c-hGH, and also via other routes, were subsequently released by other researchers.
Collinge and colleagues reasoned that individuals exposed to contaminated c-hGH, who did not succumb to CJD and lived longer, might eventually develop Alzheimer’s disease. “However, until now, there have been, to our knowledge, no clinical (that is, premortem) descriptions of iatrogenic disease caused by Aβ transmission in c-hGH recipients, despite the substantial experimental evidence for transmission via this route.”
Their newly released report describes eight people referred to UCLH’s National Prion Clinic at the National Hospital for Neurology and Neurosurgery in London, who may have developed AD as a result of c-hGH therapy. Each individual had been treated with c-hGH during childhood, often over several years. All individuals had received c-hGH prepared using the Wilhelmi or Hartree-modified Wilhelmi preparation (HWP) method.
The researchers reported that five of the individuals identified exhibited symptoms of dementia, and had either already been diagnosed with Alzheimer’s disease or would otherwise meet the diagnostic criteria for the condition. Another individual met criteria for mild cognitive impairment. These people were between 38 and 55 years old when they started having neurological symptoms. Biomarker analyses supported the diagnoses of Alzheimer’s disease in two patients with the diagnosis, and was suggestive of Alzheimer’s in one other person. An autopsy analysis in another individual showed Alzheimer’s pathology.
The unusually young age at which the individuals developed symptoms suggested they did not have the usual sporadic AD, which is associated with old age. For the five patients from whom samples were available for genetic testing the team also ruled out inherited Alzheimer’s disease.
“Their relatively young age makes sporadic Alzheimer’s disease unlikely, and, as inherited causes have been excluded, we considered that their symptoms and biomarker findings are a consequence of Aβ transmission from contaminated c-hGH received in childhood,” the team stated. “Taken together, the only factor common to all of the patients whom we describe is treatment with the HWP subtype of c-hGH. Given the strong experimental evidence for Aβ transmission from relevant archived HWP c-hGH batches, we conclude that this is the most plausible explanation for the findings observed. The clinical syndrome developed by these individuals can, therefore, be termed iatrogenic Alzheimer’s disease, and Alzheimer’s disease should now be recognized as a potentially transmissible disorder.”
As c-hGH treatment is no longer used, there is no risk of any new transmission via this route, and there have been no reported cases of Alzheimer’s acquired from any other medical or surgical procedures. There is no suggestion that amyloid-beta can be passed on in day-to-day life or during routine medical or social care.
First author Gargi Banerjee, PhD, at UCL Institute of Prion Diseases asserted, “We have found that it is possible for amyloid-beta pathology to be transmitted and contribute to the development of Alzheimer’s disease. This transmission occurred following treatment with a now obsolete form of growth hormone, and involved repeated treatments with contaminated material, often over several years. There is no indication that Alzheimer’s disease can be acquired from close contact, or during the provision of routine care.”
However, the researchers caution that their findings highlight the importance of reviewing measures to ensure there is no risk of accidental transmission of amyloid-beta via other medical or surgical procedures which have been implicated in accidental transmission of CJD.
Collinge stated, “… the recognition of transmission of amyloid-beta pathology in these rare situations should lead us to review measures to prevent accidental transmission via other medical or surgical procedures, in order to prevent such cases occurring in future. Importantly, our findings also suggest that Alzheimer’s and some other neurological conditions share similar disease processes to CJD, and this may have important implications for understanding and treating Alzheimer’s disease in the future.”
Further, the team pointed out in their paper, “Our cases suggest that, similarly to what is observed in human prion diseases, iatrogenic forms of Alzheimer’s disease differ phenotypically from sporadic and inherited forms, with some individuals remaining asymptomatic despite exposure to Aβ seeds due to protective factors that, at present, are unknown.”
Co-author Jonathan Schott, MD, at UCL Queen Square Institute of Neurology, honorary consultant neurologist at UCLH, and chief medical officer at Alzheimer’s Research UK, added, “It is important to stress that the circumstances through which we believe these individuals tragically developed Alzheimer’s are highly unusual, and to reinforce that there is no risk that the disease can be spread between individuals or in routine medical care. These findings do, however, provide potentially valuable insights into disease mechanisms, and pave the way for further research which we hope will further our understanding of the causes of more typical, late onset Alzheimer’s disease.” The authors pointed out, “Additionally, the extent to which prion-like mechanisms are involved in Alzheimer’s pathogenesis may have important bearings on therapeutic strategies targeting disease-related Aβ assemblies.”
In an associated News & Views, Mathias Jucker, PhD, at Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases (DZNE), and Lary C. Walker, PhD, at the Department of Neurology and Emory National Primate Research Center, Emory University, added, “From a practical standpoint, this report reinforces the potential of amyloid-β seeds as targets for early prevention, and it underscores the importance of informed caution in the preparation of surgical instruments, handling of tissues, and implementation of therapeutic biologics, particularly those derived from human sources.”
From a theoretical standpoint, they noted, the findings lend new support to the hypothesis that Alzheimer’s disease bears fundamental etiologic similarities to prion diseases. Accumulating data, they added, suggest that many other diseases, potentially including Parkinson’s disease and amyotrophic lateral sclerosis, may also result from the seeded aggregation of disease-specific proteins. The findings reported by Collinge et al lend what Jucker and Walker suggest is “evidential traction to longstanding speculation that prion diseases might furnish mechanistic insights into other degenerative diseases. Given the growing list of disorders in which misfolded proteins are a defining feature, the expanded prion paradigm may well become one of the most important disease principles to have emerged in the past 50 years.”
