The headlines are, at a minimum, a bit sensational: “Alzheimer’s can be transmitted between people.” “What you need to know about Alzheimer’s spreading between humans.” “First evidence of human-to-human transmission of Alzheimer’s disease.”
The nuance, thankfully, is far less frightening, at least from a public health standpoint. A case series published Jan. 29 in Nature Medicine by scientists at University College London reported that five patients who were given growth hormones derived from human cadavers as part of a now-obsolete childhood medical treatment later developed early-onset Alzheimer’s disease.
“This is not a public health crisis by any means. It’s not like we’ve discovered any kind of transmission outside of this rare treatment,” Keith Vossel, M.D., director of the Alzheimer’s Research Center at the University of California, Los Angeles, assured Fierce Biotech Research. But it is the first documented instance of Alzheimer’s disease being contracted iatrogenically, or via a medical procedure, he said.
The tragic cases also strengthen some researchers’ hypothesis that the amyloid beta plaques thought to drive the condition behave like prions, self-perpetuating misfolded proteins that cause severe brain disease.
“I wouldn’t go so far as to say that it validates a theory, but I think it just adds one more strong piece of evidence for the prion-like hypothesis of Alzheimer’s seeding and trans-synpatic spreading,” said Vossel, who was not involved with the new research.
So how did the patients in the case series wind up with Alzheimer’s? Call it a major medical mishap: They were part of a cohort of more than 1,800 people who, between the years of 1959 and 1985, were treated for various diseases with injections of human cadaveric pituitary-derived growth hormone, or c-hGH. Unbeknownst to the clinicians performing the treatment, the c-hGH contained amyloid beta plaques, presumably from the brains of the deceased donors. The treatment also contained other prions that led to at least 200 other patients developing Creutzfeldt-Jakob disease, a rapidly progressive neurodegenerative prion disease, as the researchers reported in an earlier paper.
In the three to four decades following, five of the eight patients described in the case series developed Alzheimer’s, most of them during their late 30s and 40s. Two of the others had some degree of cognitive impairment while the last one was asymptomatic. Analyses conducted after they died revealed that all eight patients had some signs of Alzheimer’s pathology, such as the presence of amyloid beta plaques or brain volume changes, including the patient who didn’t show symptoms before death. Notably, they had varying degrees of the cerebral vessel disease that’s typically associated with Alzheimer’s, suggesting their form of the condition might be unique.
To rule out genetic causes, the University College London team ran genomic analysis to look for gene mutations linked to neurodegenerative disease on five of the patients. (Samples weren’t available for the other three.) Aside from a single risk allele in a gene associated with Alzheimer’s in one case—which is far from a guarantee of developing the disease—the researchers didn’t find any variants that could explain what happened.
After examining all the other factors over the course of the patients’ lives that could have led them to develop Alzheimer’s so young, the researchers asserted that the contaminated c-hGH was to blame. Their conclusion was bolstered by findings from a mouse study they published back in 2019 in which mice that were injected with some of the same c-hGH from the period developed amyloid beta plaques in their brains.
If iatrogenic transmission did indeed occur in these patients via prions, this could have implications for the scientific understanding of Alzheimer’s and for designing drugs to treat it, the University College London scientists wrote in their paper. Prions come in different strains that can differ in how quickly they replicate within tissues, move between tissue types and are cleared by the body, as this review in Nature explains. If amyloid beta plaques are prions, and a therapy targets only the most common strain, treatment could ultimately backfire.
“Structurally diverse [prion forms], present as minor components, may be selected for propagation by a drug that binds to the dominant species, potentially leading to the development of resistance,” the researchers wrote. Other scientists have found evidence of amyloid beta strains in microscopy studies, they noted. On top of that, the patients in the case series presented differently than those who develop Alzheimer’s due to genetics, with earlier disease onset and more rapid progression but without a clear pattern of blood vessel disease.
“We hypothesize that iatrogenic [amyloid-beta disease] caused by c-hGH can result in a clinical phenotype (possibly mediated by amyloid-beta strain type), in which clinical [blood vessel disease] is less prominent,” the researchers wrote. “Additionally, it is entirely possible that some iatrogenic cases of Alzheimer’s disease may differ markedly from sporadic and inherited forms … the full spectrum of dementias caused by amyloid-beta transmission remains to be elucidated.”
Yet despite the evidence so far, Vossel believes the findings are still vulnerable to what he described as a “referral bias.” While the patients were young and lacked genes that would predispose them to Alzheimer’s, it’s still possible that they would have ultimately developed the disease anyway, Vossel said.
“I think a lot of people assume that if someone has early Alzheimer’s disease that it should be genetic in cause, but the truth is that most Alzheimer’s disease is sporadic in nature,” he said. “I think it’s a little premature to put too much weight on this one article. We can gather more information.”