Up until 1985, one treatment for children with growth deficiencies was nonrecombinant human pituitary growth hormone from the pituitary glands of deceased individuals. Such treatment was discontinued when it was discovered that along with growth hormone, the extracts could contain the prion protein that is the cause of Creutzfeldt-Jakob disease (CJD).
But now, researchers have discovered that the treatments appear to have come with another health risk.
Autopsies have found evidence of amyloid-beta pathology – the anatomical calling card of Alzheimer's disease – in seven of eight formerly growth hormone-treated patients. In four of those patients, the pathology was "really quite significant and in some cases severe," John Collinge of the British MRC prion unit told reporters at a press conference announcing the findings, which were also published in the Sept. 10, 2015, issue of Nature.
The patients, who died of CJD, ranged in age from 36 to 51. Collinge said that absent a genetic predisposition to Alzheimer's, which none of the individuals in the study had, "in that age group, you really don't see this sort of pathology."
He concluded, "the most likely explanation is that the growth hormone preparation with which these people were treated as children, in addition to being contaminated with CJD prions, was probably also contaminated with [amyloid]-beta seeds."
Collinge stressed that the patients his team looked at did not have clinical evidence of Alzheimer's disease, or even some of the anatomical features of advanced Alzheimer's disease such as tau tangles. It is impossible to know whether they would have gone on to develop such symptoms if they had lived longer.
He also noted that the work he and his colleagues have published "relates to a very special situation, where people have been injected with human protein. . . . In no way is this suggesting that Alzheimer's is in any way a contagious disease."
One exception is that certain medical and surgical procedures might be able to transmit amyloid-beta seeds. Prion proteins are notoriously hard to destroy, and the same might be true for the seed protein of Alzheimer's disease, whatever it may be.
One of the important implications of the work is that it points to a need to develop assays that can identify and quantify that seed.
"We don't really know what the seed is yet," Collinge said, either in terms of its structure or in terms of how aggregation proceeds.
For now, the existence of seeds in neurodegenerative disorders is demonstrated practically – brain homogenates from disease models are injected into experimental animals and if the recipient develops neurodegenerative disease, a seed was present.
But unlike with prion proteins, there are no biochemical assays to determine there are a certain number of amyloid beta seeds per mL of brain homogenate, because the nature of the seed is unknown. Collinge said such assay development is now an "active area of research in his unit."
Some experts were skeptical that the work is indicative of amyloid seeds at all.
David Allsop of the University of Lancaster said in a prepared statement that "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 beta amyloid)."
But Collinge said he thought such a trigger hypothesis was unlikely.
"There was no coincidence of the pathologies, they were in different parts of the brain, and so it didn't look like they were directly related," he told reporters.
Scientifically, Collinge said, the work is "illustrating this growing paradigm shift," where researchers increasingly realize that seeding may play a role in a number of neurodegenerative diseases. (See BioWorld Today, Sept. 22, 2006.)
"We used to think of prion disease as being very special" in being seeded by multiple potential mechanisms, Collinge said. "What we're now coming around to realize is that these proteopathic seeds which can grow and spread in the brain may well be relevant to Alzheimer's disease, Parkinson's disease, and some other neurodegenerative diseases as well."
Seeding's possible broader contribution to neurodegeneration might also open up new therapeutic avenues.
In prion diseases, there is some evidence that targeting normal prion protein can halt and even reverse the course of prion disease.
Prion disease progresses because misfolded versions of prion proteins induce misfolding in normal prion proteins they come into contact with, and "you can stop these protein polymerizations by sequestering the normal protein and preventing it acting as fuel," Collinge said.
His team hopes to start clinical testing of antibodies that sequester normal prion protein within the next year.
"There's in principle no reason something similar shouldn't work in Alzheimer's disease," he said.
In Alzheimer's disease, attempts to break up amyloid plaques have focused on the aggregates themselves, and on the misprocessed protein – attempts that, as Collinge rather delicately put it, "have not been particularly successful."