The unsettling evidence that Alzheimer’s disease may be transmissible under limited—but definitely nonzero—circumstances keeps growing.
Last December I wrote about research that revealed that infectious, lethal proteins called prions have the potential to be transmitted on optical medical equipment because they are present throughout the eyes of victims.
This was all the more disturbing in light of a study I had also recently written about that suggested that peptide aggregates—essentially sticky, self-propagating clumps of misfolded protein bits collectively referred to as amyloid—found in the brains of Alzheimer’s patients may be transmissible in the same ways that prions are.
Then, just a few days after I wrote about the prion eye hazard, a new paper appeared in Nature that seemed to take the evidence for the transmissibility of Alzheimer’s peptides from “circumstantial” to “experimentally produced.” It is fascinating, if unsettling, news, that further blurs the line between amyloid and prions.
Human prion diseases are rare. Prions usually form spontaneously or are inherited via faulty genes, but sometimes find their way into humans through consumption of contaminated brain or spinal cord tissue. In the case of mad cow disease, it happened via contaminated beef.
In rare cases (so far as we know), human prion transmission has happened when surgical instruments used on an infected patient were cleaned and reused on an uninfected one. Prions stick to steel like glue, are stable for decades at room temperature, and survive a bombardment of chemical and physical cleaning assaults that are more than sufficient to obliterate other pathogens. Prions are survivors.
In the original Alzheimer’s transmissibility study, scientists examined the brains of eight patients treated with prion-contaminated human growth hormone as children who decades later died from prion disease (out of over 30,000 people so treated, more than 200 died this way).
The hormone had become contaminated with prions because it had been extracted from cadavers—one or a few of whom presumably died of prion disease—and processed in such a way that the prions remained. Of course, prions are not the only misfolded proteins that potentially lurk in the brains of cadavers.
The researchers discovered the brains of seven of the eight contained, in addition to prions, peptide aggregates called amyloid beta (Aβ for short). Aβ is a collection of misfolded peptides whose correctly folded versions are present in the human brain and perform a variety of mid-level tasks. When the misfolded versions form, they behave like prions, catalyzing the conversion of healthy forms into diseased ones and accumulating in clumps called plaques. Indeed, past experiments have shown that injecting small amounts of human Aβ into the brains of primates or of mice bred to express a humanized form of the Aβ precursor protein generates Aβ plaques in these animals.
Plaques are characteristic of and possibly the instigators of Alzheimer’s disease when they accumulate around neurons in the brain. However, the seven brains did not have plaques. The Aβ in these brains had built up in the walls of blood vessels, where such accumulations can cause bleeding and dementia. This condition is called cerebral amyloid angiopathy, and it co-occurs with most Alzheimer’s disease but can also strike on its own.
The eight victims had all still been young enough that their brains would not be expected to show any signs of Alzheimer’s or cerebral amyloid angiopathy unless they had genetic risk factors. Understandably, given the implications, the scientists who studied their brains were concerned.
The December Nature study was authored by this same team. In it, they revealed that they had managed to get their hands on original vials of prion-contaminated growth hormone that had been helpfully squirreled away for decades by Public Health England.
They tested the samples for both Aβ peptides and tau, another protein that builds up in the brains of Alzheimer’s patients and causes its other brain pathology: tangles. Indeed, two types of Aβ and tau were still present in the vials, even after more than three decades of room temperature storage. Aβ and tau, at least, are survivors too.
This team took their study a step further by injecting a tiny sample of these vintage vials into the brains of mice engineered to be susceptible to human Alzheimer’s. The mice developed both Aβ plaques and cerebral amyloid angiopathy, although they showed no signs of tau. Aβ peptides had not only managed to survive decades of room-temperature storage, they were also still transmissible. This is concerning.
It is important—imperative—to emphasize that transmissible does not equal contagious. There is absolutely no evidence that people with dementia can spread their disease casually to people around them. Even donated blood appears to be safe, as no association with blood transfusions and Alzheimer’s disease has ever been detected.
Rather, in the course of some neurological surgeries—and perhaps certain kinds of medical exams—prions may become lodged on equipment. And there is a chance this equipment could transmit the disease. Organ donation protocols may also warrant some review. It was already known that donations of dura mater, a tough brain covering, have transmitted Aβ to young people in the past.
And I wonder. Since Alzheimer’s disease is so common, and we have not (to my knowledge) been looking for Alzheimer's caused by surgical or other medical procedures that access eye or neural tissue—particularly in patients for whom the appearance of Alzheimer’s would not be surprising—is it possible that we are underestimating the transmission potential of this disease, and that such events are less rare than we would guess?
Alzheimer’s is not the only neurodegenerative disease in which aggregating misfolded host proteins—a class referred to as amyloid—seem to propagate and wreak havoc either. In Parkinson’s disease, misfolded alpha-synuclein proteins spread through the brain, and in amylotrophic lateral sclerosis (Lou Gehrig’s disease), the misfolded, accumulating protein is TDP-43. We should investigate the transmission potential of these diseases as well.
The only thing that seemed to separate these conditions from classic prion diseases was transmissibility. But now that that barrier has been breached for at least one, I also wonder: What is the difference between amyloid and prions? Are they part of a spectrum? Are they one and the same? If not, what is the difference? Can what we’ve learned about the biology of prions help our efforts to fight amyloid dementias? Of course, since we still can’t cure prion diseases, it may not be much help even if so.
The realization that the peptides involved in some of the most common and feared dementias on Earth may be transmissible under even limited conditions is a sobering and humbling reminder of how very little we still understand about them. Given what we know about prions, I think we would be wise not to underestimate their abilities.