10 September 2015
New Clinical Study Strengthens the Possibility that the Dissemination of Misfolded Proteins May Contribute to Alzheimer's Disease
A study published in Nature presents an interesting observational study on a small number of patients who had acquired CJD following treatment with growth hormone derived from human brain tissue - human-derived growth hormone has not been used since 1985.
In addition to having prion disease, some of the patients presented in this study showed some of the brain changes that are observed in Alzheimer’s disease, namely the deposit of misfolded proteins called amyloid plaques. However, none of the patients showed other brain changes, called tau tangles, which are characteristic of the clinical development of Alzheimer’s and thought to be the cause of the cognitive decline observed in patients with the disease.
This clinical observation supports previous findings in mice that the introduction of amyloid ‘seeds’ into brain tissue can lead to the production of larger amyloid plaques that are associated with Alzheimer's disease. The concept that ‘seeding’ is involved in the progression of Alzheimer's and other neurodegenerative disorders in the brain is an area of intense study in a number of laboratories worldwide, this study provides important new information in the human context.
Amyloid beta pathology in the grey matter and blood vessel walls characteristic of Alzheimer’s disease (AD) and the related cerebral amyloid angiopathy (CAA) was observed in the brains of deceased patients who acquired Creutzfeldt–Jakob disease (CJD) following treatment with prion-contaminated human growth hormone. Although there is no evidence that human prion disease, AD or CAA is contagious (spread from person to person by direct contact), the study of eight patients, published in this week’s Nature, suggests that amyloid beta (the peptides that form the main components of the amyloid plaques found in the brains of patients with AD) may potentially be transmissible via certain medical procedures.
Human transmission of prion disease has occurred as a result of various medical procedures (iatrogenic transmission), with incubation periods that can exceed five decades. One such iatrogenic route of transmission was via the treatment in the UK of 1,848 persons of short stature with human growth hormone (HGH) extracted from cadaver-sourced pituitary glands, some of which were inadvertently prion-contaminated. The treatments began in 1958 and ceased in 1985 following reports of CJD among recipients. By the year 2000, 38 of the patients had developed CJD. As of 2012, 450 cases of iatrogenic CJD have been identified in countries worldwide after treatment with cadaver-derived HGH and, to a lesser extent, other medical procedures, including transplant and neurosurgery.
Professor John Collinge, from the MRC Prion Unit, Sebastian Brandner and colleagues conducted autopsy studies, including extensive brain tissue sampling, of eight UK patients aged 36–51 with iatrogenic CJD. The authors showed that in addition to prion disease in all eight brains sampled, six exhibited some degree of amyloid beta pathology (four widespread) and four of these had some degree of CAA. Such pathology is rare in this age range and none of the patients were found to have mutations associated with early-onset AD. There were no signs of the tau protein pathology characteristic of AD, but the full neuropathology of AD could potentially have developed had the patients lived longer. The authors examined a cohort of 116 patients with other prion diseases and found no evidence of amyloid beta pathology in the brains of patients of similar age range or a decade older who did not receive HGH treatment.
Professor Sir John Savill, chief executive of the Medical Research Council, said:
”These preliminary findings should stimulate further research into the possibility that amyloid seeds might be involved in dissemination of pathology within a brain that goes on to develop classical features of Alzheimer’s disease. The work does not warrant some of the more speculative media reports seen so far, and currently there is no evidence from a wide range of studies to suggest that Alzheimer’s disease can pass from one individual to another.”
“The Medical Research Council undertakes discovery research to improve the health of the public who fund us, and we will continue to fund research exploring the biological basis for Alzheimer’s disease and will work with other stakeholders to consider incisive follow-on research proposals. I hope we can count on patients and the public to participate in such research if needed.”
Following suggestions in some media that there could be a risk of Alzheimer’s disease being transmitted to patients via dental surgery, Professor John Collinge issued the following clarification:
“Our findings relate to the specific circumstance of cadaver-derived human growth hormone injections, a treatment that was discontinued many years ago.
“It is possible our findings might be relevant to some other medical or surgical procedures, but evaluating what risk, if any, there might be requires much further research. Our current data have no bearing on dental surgery and certainly do not argue that dentistry poses a risk of Alzheimer’s disease.”
The paper, entitled Evidence for human transmission of amyloid-ß pathology and cerebral amyloid angiopathy by Collinge, Brandner et al, is published in Nature.
Representation of beta-amyloid plaques.