LONDON — There was something odd about these Alzheimer’s cases.
Part of it was the patients’ presentations: Some didn’t have the classic symptoms of the condition. But it was also that the patients were in their 40s and 50s, even their 30s, far younger than people who normally develop the disease. They didn’t even have the known genetic mutations that can set people on the course for such early-onset Alzheimer’s.
But this small handful of patients did share a particular history. As children, they had received growth hormone taken from the brains of human cadavers, which used to be a treatment for a number of conditions that caused short stature. Now, decades later, they were showing signs of Alzheimer’s. In the interim, scientists had discovered that that type of hormone treatment they got could unwittingly transfer bits of protein into recipients’ brains. In some cases, it had induced a fatal brain disease called Creutzfeldt-Jakob disease, or CJD — a finding that led to the banning of the procedure 40 years ago.
It seemed that it wasn’t just the proteins behind CJD that could get transferred. As the scientific team treating the patients reported Monday in the journal Nature Medicine, the hormone transplant seeded the beta-amyloid protein that’s a hallmark of Alzheimer’s in some recipients’ brains, which, decades later, propagated into disease-causing plaques. They are the first known cases of transmitted Alzheimer’s disease, likely a scientific anomaly yet a finding that adds another wrinkle to ongoing arguments about what truly causes Alzheimer’s.
“It looks real that some of these people developed early-onset Alzheimer’s because of that [hormone treatment],” said Ben Wolozin, an expert on neurodegenerative diseases at Boston University’s medical school, who was not involved in the study.
Other outside scientists agreed that they found the findings legitimate, in particular because only people who had received cadaveric growth hormone prepared in a particular way — a method that doesn’t eliminate protein bits — went on to develop dementia.
Such incidents of illness are known as “iatrogenic,” meaning the result of a medical procedure. In conditions like iatrogenic CJD, the transmissible agents are known as prions — basically, misfolded pieces of protein that go on to cause disease, like a sort of infectious bug.
Researchers debate the definition of a prion and whether it could include amyloid. But regardless, the paper’s authors “provide tantalizing evidence that, under extraordinary circumstances, Alzheimer’s disease is transmissible by a prion-like mechanism,” Mathias Jucker of Germany’s University of Tübingen and Lary Walker of Emory University wrote in a commentary also published Monday.
Both the study’s authors and outside researchers stressed Alzheimer’s is not some contagious disease that you could catch by caring for a relative, for example. Cases tied to cadaveric growth hormone treatment are also no longer possible; a synthetic hormone has been used instead for decades. The paper’s authors, who run a special prion disease research and treatment center in London, describe just five Alzheimer’s patients out of the more than 1,800 people who were known to have received cadaveric growth hormone in the U.K. from 1959 to 1985. Still, the researchers said the findings were a reminder of the continuing importance of practices like sterilizing neurosurgical instruments, which, in theory, could transfer prions if not properly cleaned between patients.
But in addition to being a scientific curiosity — and another example of the fallout of the use of cadaveric growth hormone — these cases could also stir up the decades-long, oft-contentious fight over the roots of Alzheimer’s.
“We think from a public health point of view, this is probably going to be a relatively small number of patients,” said John Collinge of the MRC Prion Unit at University College London, the senior author of the paper. “However, the implications of this paper we think are broader with respect to disease mechanisms — that it looks like what’s going on in Alzheimer’s disease is very similar in many respects to what happens in the human prion diseases like CJD, with the propagation of these abnormal aggregates of misfolded proteins and misshapen proteins.”
Many scientists believe that beta-amyloid plays a role in the development of Alzheimer’s, and therapies that can clear the protein from people’s brains have finally, after decades of failed attempts, started showing some benefits for patients. But most experts also think amyloid isn’t solely responsible. So in these cases, was there something else going on in addition to the amyloid transfer?
“It raises questions about whether amyloid alone is able to cause problems,” said Marc Dhenain, an Alzheimer’s expert at the French research center CEA, who was not involved in the new study.
Outside researchers said they were also left scratching their heads about some of the findings. They said there was limited information, with findings reported from just a few patients, and data like genetic sequencing and autopsy results available from just a sample of them.
They noted, however, that there didn’t seem to be much inflammation in the patients’ brains, another hallmark of Alzheimer’s that can be induced by amyloid. They also wondered why there was so little presence of another protein called tau in the people’s brains despite their cognitive losses, even though tau levels often correlate to cognitive decline. Some researchers speculated that the patients may have had some other genetic mutation that could increase their risk of Alzheimer’s. Two of the patients had intellectual disabilities, another risk factor.
“Can the pathology be transmitted? Yes, it can, and that’s important conceptually,” Wolozin said. “The question is, what’s driving disease? There are many weird things about these rare cases. What’s unclear from the images is, why would they develop such severe dementia that quickly?”
Globally, more than 200 cases of iatrogenic CJD have been documented in recipients of cadaveric human growth hormone, with the bulk of patients in France, the U.K., and the U.S. And for years, researchers have been gathering clues that there may be an iatrogenic form of Alzheimer’s as well. (The vast majority of Alzheimer’s cases are what’s known as sporadic, developing among older people. There are also some early-onset cases that are tied to inherited mutations.)
In 2015, the UCL prion researchers reported finding lots of beta-amyloid in the brains of patients who died of iatrogenic CJD, including a buildup in the brain’s blood vessels, which is known as cerebral amyloid angiopathy and which is seen in most people with Alzheimer’s. It led them to hypothesize that the hormones the patient received had been contaminated not just with the CJD prions, but seeds of amyloid as well. It also made them wonder whether the patients, had CJD not killed them, would have gone on to develop Alzheimer’s.
The paper describes eight patients who were treated at the U.K.’s National Prion Clinic from 2017 to 2022, none of whom had CJD and only some of whom were found to have Alzheimer’s. They had received the hormone treatment as children for different causes of short stature: some had brain tumors, others had developmental conditions, others just lacked their own natural hormone.
Five of them had been diagnosed with Alzheimer’s or likely had Alzheimer’s disease, with their symptoms starting between the ages of 38 and 55. Among the other three patients, two had some cognitive impairments, while the third was asymptomatic.
The researchers noted that the presentation of iatrogenic CJD often differs from that of the more common sporadic cases, so it’s possible the transmitted Alzheimer’s cases would look somewhat distinct from typical cases.
Gargi Banerjee, the lead author of the paper, said the UCL researchers considered other possible causes of these patients’ Alzheimer’s. Given the age of the patients, these weren’t sporadic cases, which almost always develop only later in life. The patients didn’t have known genetic mutations that could cause early-onset dementia. The researchers also considered the underlying reasons why the patients had received the hormone in the first place — was it a result of their cancer treatment or congenital conditions? — but that wasn’t a likely explanation either.
“The thing about this group is thinking about them as a whole,” she said. “In the people who did have symptoms, they had various different illnesses, but the only combined fact was that they all had this particular type of growth hormone, this particular preparation in childhood. … There was no other unifying cause for this.”