A group from the University College London (UCL), Institute of Prion Diseases has put another puzzle piece in place in the case of deaths caused by human cadaveric growth hormone (c-hGH.) Some people who had received the c-hGH as children to help stimulate growth died of Creutzfeldt–Jakob disease (CJD)—transmissible spongiform encephalopathy characterized by progressive and irreversible brain damage.

CJD results from the accumulation of prion proteins—normal brain constituents that can become misshapen, stick together, and accumulate in the brain. It is the buildup of prion proteins that causes progressive damage to the brain.

John Collinge, M.D., an expert in prion proteins and professor of neurology and head of the department of neurodegenerative disease at the UCL Institute of Neurology, was in the process of examining the patients’ brains for prions when his group found the presence of Aβ buildup. Aβ pathology is a hallmark of cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD). Several of the patients displayed pathology resembling CAA; however, none met the full neuropathological criteria for AD.

These unusual findings were very surprising, Dr. Collinge noted, mostly because the patients were only in their 30s and 40s—far younger than normal patients with this type of pathology. A 2015 Nature paper that reported these findings, “Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy” was just the start of Dr. Collinge’s sleuthing. In it, the researchers hypothesized that the c-hGH batches may have been contaminated with seeds of Aβ and/or prions. However, further investigation was required to determine whether the c-hGH samples were contaminated with Aβ.

The team first set out to identify the vials of growth hormone. With some detective work and much luck, they found some of the original material in an archive and were able to identify the same material that had been injected into the patients. They were particularly interested in the vials that were prepared by HWP—a method that didn’t use chromatographic purification and could potentially have included contaminants. A collaborating team of researchers at Harvard Medical School identified both Aβ and tau (a hallmark of AD) in the samples.

In order to test if these samples could seed the Aβ pathology in healthy organisms, the team collaborated with researchers at RIKEN in Japan to obtain genetically modified mice that expressed a mutated, humanized version of the amyloid precursor protein (APP) gene and developed the first signs of Aβ deposition at around six months of age. Female mice aged 6–8 weeks received injections of the original c-hGH samples directly into the brain. Groups of mice were also injected with synthetic growth hormone as a negative control and tissue from patients who died of AD as a positive control. After eight months, the mice were killed and their brains examined. The team found Aβ deposits and CAA were consistently found in mice that received the original c-hGH samples but were almost completely absent in the control mice. This work was published in the paper titled, “Transmission of amyloid-β protein pathology from cadaveric pituitary growth hormone” and was published in Nature on December 13.

The research team plans to further investigate the seeding potential of the tau detected in the c-hGH samples, something that will require experimentation using a separate tau mouse model.

Although the team was not surprised by the results, per se, as they supported their hypothesis, Dr. Collinge said that he “was rather amazed that we could seed so easily from this material that had sat around as a dry powder for 30–40 years.”

Although Alzheimer’s pathology may be transmissible, Dr. Collinge noted that “there is no suggestion that Alzheimer’s is a contagious disease. You cannot catch it through intimate contact.” However, this finding adds some weight to the idea that, in some rare cases, Aβ can travel from one person’s brain to another.

Although the preparation of hGH was switched from the pituitary glands of cadavers to a safer, recombinant form in 1985, after it had the realization that some batches were contaminated with CJD prions, there may still be practical considerations that stem from this finding. The authors wrote, “This experimental confirmation has implications for both the prevention and the treatment of AD, and should prompt a review of the risk of iatrogenic transmission of Aβ seeds by medical and surgical procedures long recognized to pose a risk of accidental prion transmission.” Because Aβ seeds and prions can stick to metal, metal instruments and implants used during brain surgery are of particular interest. Equally as important as the caution regarding transmission is what this study indicates about Aβ seeds, furthering our understanding of the biology that surrounds CJD and AD.