First case reports of cadaver-to-human transmission of Alzheimer's disease
First case reports of cadaver-to-human transmission of Alzheimer's disease
Scientists may have found the first evidence of iatrogenic transmission of Alzheimer's disease in humans
Happy Tuesday! I am guessing that most of you have might heard about the Nature Medicine paper that was making headlines yesterday. Researchers from the MRC Prion Unit at University College London (UCL) have published what might be the first-ever case reports of iatrogenic Alzheimer’s disease caused by a medical treatment for dwarfism—human cadaver-derived growth hormone injection—that was in wide practice before 1985.
I usually don’t make efforts to summarize papers on Twitter that are too popular and everyone is talking about. I simply retweet someone else’s thread, perhaps with a quote, and focus on other interesting papers that people haven’t noticed yet. But after I’ve started writing the Substack newsletter regularly, I feel I should probably document important moments in medical history like this in the GWAS Stories. Some day when I look back on scientific happenings from this period, these posts will help refresh my memory.
The most fascinating part of this new paper is the background story. This is one of those rare papers, where the background of the study is much more interesting than the actual study itself.
So, the story begins more than half a century ago, sometime in the 1950s, when a miraculous treatment emerged for the treatment of dwarfism and other pituitary hormone deficiencies, caused by genetic mutations or surgical resection of pituitary brain tumours.
Here is a screenshot of a letter to the editor published in the Journal of Clinical Endocrinology and Metabolism in 1958, one of the first reports of clinical trials testing the efficacy of growth hormone extracted from brain tissues of dead people in treating dwarfism. Remember, this was in 1958, even before the Declaration of Helsinki, the cornerstone document of human research ethics came into existence. So, it shouldn’t be a surprise that scientists had just started to learn to extract and process hormones from cadaver brain tissues but they were already running human trials.
Inspired by the impressive outcomes of initial trials in the US, the UK followed suit launching their trials the very next year, the successes of which would eventually lead to the launch of a nationwide health program in the UK in 1976 for the treatment of short stature using cadaver-derived growth hormone. Little did the scientists know that some of the batches of hormones they were injecting into the children contained seeds of misfolded prion proteins that would bring death sentences to not only many of the patients but ultimately, to the whole health program.
The first reports of deaths in patients who received the human growth hormone surfaced in 1985 both in the USA and UK. Post-mortem examinations revealed that all the deaths were due to a prion disease called Creutzfeldt–Jakob disease (CJD). The worldwide panic caused by the reports led the government to permanently shut down the treatment program. But it was too late. By then, more than 30,000 children were already dosed, who would later become the subjects of what might be the longest natural history study in medical history, running for more than 40 years to date (because the incubation period of CJD varies widely from anywhere between a few years to up to 30 years or even more).
One major revelation of the postmortem studies of the patients who died of CJD from human growth hormone treatment was the discovery of amyloid beta protein aggregates in the grey matter resembling Alzheimer’s pathology and in the blood vessels resembling the cerebral amyloid angiopathy (CAA), the work published in Nature in 2015 by some of the same authors of the current paper from the MRC Prion Unit at UCL. This was probably the first clue that led scientists to speculate that Alzheimer’s disease (or at least a pathology similar to Alzheimer’s), similar to prion diseases, could be transmitted from one human to another via infectious proteins, and there might be commonalities between prion diseases and Alzheimer’s disease.
The same research team later published another major finding in Nature in 2018, showing that the archived hormone vials from the same batches as the vials used in patients who died of CJD contained substantial levels of abeta and tau proteins. Not only that, the authors further experimentally proved that these seeds of amyloid proteins were capable of forming amyloid beta plaques and CAA in mouse models of Alzheimer’s disease.
Although there were overwhelming pieces of evidence to suggest that some of the patients who received the cadaver-derived growth hormone might develop Alzheimer’s disease, no clinical reports of Alzheimer’s disease in patients with a history of growth hormone treatment during childhood surfaced until a few years ago.
Between 2017 and 2022, eight patients were referred to the UK’s National Prion Clinic (NPC) with neurological symptoms. It turned out that four of these eight patients were among the unfortunate who received the growth hormone from vials that were previously found to be contaminated with amyloid seed proteins. Clinical diagnostic workup revealed that none of these eight individuals had symptoms or biomarkers suggestive of CJD but instead had features suggestive of early-onset Alzheimer’s. Genetic testing excluded known Alzheimer’s genetic mutations in APOE or APP, suggesting that these patients are most likely suffering from an iatrogenic form of Alzheimer’s disease caused by the growth hormone injections they received when they were children.
Though the whole story is extremely fascinating, we should note that the conclusions of the study are based on a strong prior that human growth hormone treatment is capable of causing Alzheimer’s disease. Chances that Alzheimer’s in these patients could be caused by other factors cannot be completely excluded. However, when looked in the light of its 50-year history, the findings are too compelling to attribute to anything else other than the growth hormone treatment.
