Researchers Find Evidence of Human-to-Human Spread of Alzheimer’s Protein Aggregates

by Jim Schnabel

September 9, 2015

Scientists have long known that the amyloid beta (Aβ) aggregates found in the brains of people with Alzheimer’s disease can proliferate in an infection-like manner in a lab dish, as the clumped Aβ proteins coax individual Aβ proteins into joining them. Researchers also know that these tough aggregates appear to multiply and spread through the brain during the course of Alzheimer’s disease.

Experiments in mice and monkeys have even shown that Aβ aggregates taken from one brain can seed the formation and spread of new aggregates in another.

Yet everyone has assumed that the transmission of Aβ pathology never happens in humans.

That assumption must now be set aside. Researchers from the UK’s Medical Research Council report in Nature today that a no-longer-used growth hormone treatment, derived from the brains of dead people, appears to have spread Aβ pathology to some recipients.

“We think we’re seeing this now in these patients because there has been a 30-40 year period elapsed—this is probably the length of time it takes for this pathology to develop in the brain,” said senior author John Collinge in a conference call with reporters this week.

Although some of those who received the contaminated hormone treatment in the past may go on to develop dementia as a result, such cases—of medical-induced or “iatrogenic” Alzheimer’s—would probably be very rare, so there is no cause for general alarm.

But the medical science community will now be looking very carefully at other possible routes of transmission. Moreover, if scientists confirm that Aβ pathology, and Alzheimer’s, is truly transmissible, it would mean in effect that Alzheimer’s is not like a prion disease—as some have argued for decades—it is a prion disease.

An unexpected discovery

The finding originated from an autopsy study of people who had received human growth hormone (HGH) treatments, mostly in childhood, for a form of dwarfism. Nowadays medical HGH is made in large cell cultures, using biotech methods. But from 1959 until 1985, it was extracted from the pituitary glands of dead people.

The use of cadaver-derived HGH is already considered one of the great disasters of modern medicine. Each batch of the commercially made hormone was derived from the pituitary glands of many donors, and some batches turned out to contain abnormal aggregates of the human prion protein (PrP), presumably from one or more donors. These PrP aggregates—also called “prions”—cause the rapidly fatal, brain-destroying disease known as Creutzfeldt-Jakob disease (CJD).

In 1985, amid an upsurge of scientific interest in CJD and related prion diseases in animals (BSE, scrapie, chronic wasting disease), physicians realized that cadaver-derived HGH, which by then had been given to tens of thousands of patients worldwide, was responsible for some CJD cases. Cadaver-derived HGH stopped being used. But the disease incubation process was so slow—unsurprisingly, in such young brains—that recipients continued to come down with CJD for decades afterwards. To date 77 cases of iatrogenic CJD from cadaver-HGH have been recorded in the UK alone.

It was while analyzing the brains of eight such cases for the Medical Research Council’s Prion Unit, at the National Hospital for Neurology and Neurosurgery in London, that Collinge, Sebastian Brandner, and colleagues observed the unexpected Aβ pathology.

“What we found, very much to our surprise, is that of these eight patients, four of them had really quite significant, and some severe, deposition of Alzheimer’s amyloid protein in their brains,” said Collinge. “Two additional patients had patchy amyloid, one had a small amount, but only one was completely free of Aβ [deposits] in the brain.”

This was a surprising finding because the subjects had died at relatively young ages (36-51) when Alzheimer’s-like Aβ pathology is hardly ever seen.

The team checked the DNA of the patients and observed that none had mutations that would have caused or strongly predisposed them to have early Alzheimer’s.

Another possibility was that the PrP aggregates that had caused CJD had somehow “cross-seeded” Aβ aggregation. But the Aβ plaques weren’t in the same places in the brain as the PrP pathology, as the researchers would have expected in a case of cross-seeding.

A further possibility was that the CJD had induced the Aβ deposits in some other way, perhaps by exhausting the brain’s defense mechanisms against harmful protein aggregates. But the researchers checked the autopsied brains of 116 patients with other, sporadic or genetic forms of CJD, and found none of the intense Aβ pathology they had observed in the iatrogenic CJD cases. “There didn’t appear to be any association between CJD and Aβ in those brains,” Collinge said.

The researchers then did a study of pituitary glands, and found that 7 of 49 autopsied brains of mostly elderly people with noticeable Aβ deposits also had noticeable Aβ deposits in the pituitary—located at the base of the brain—which again was consistent with the hypothesis that Aβ from donor pituitaries had seeded the pathology seen in the patients.

These results didn’t prove that Aβ pathology was transmitted to the iatrogenic CJD patients, but it strongly suggested it, and went some way towards ruling out alternative possibilities.

“We think the most likely explanation is that the growth hormone preparations with which these people were treated as children, in addition to being contaminated with CJD prions, were probably also contaminated with Aβ seeds,” said Collinge. “Of the hundreds of thousands of [pituitary] glands collected over the years, to make these batches of hormone, very many will have been contaminated with Aβ, simply because Aβ pathology is very common, as is Alzheimer’s disease, in the elderly.”

Remarkably, in the iatrogenic CJD cases that showed Aβ pathology, the scientists observed none of the tau protein-based “neurofibrillary tangles” that are also seen in affected brain regions in Alzheimer’s disease. These abnormal tau formations are, however, thought to represent the later, symptomatic phase of Alzheimer’s when the extensive cell loss and sharp cognitive decline occurs—and there is some evidence that younger or simply healthier brains can delay this phase indefinitely, even when greatly burdened by Aβ.

What now?

The possibility of transmission, raised in this study, has implications for the thousands of people still living who formerly received cadaver-HGH treatments, or were subjected to other medical procedures—such as corneal transplants—that have been known to transmit CJD. It is unknown whether they are at higher risk of Alzheimer’s dementia, but researchers certainly will want to address that question in further studies.

The chance of brain hemorrhage may also be higher in such patients. Collinge and colleagues noted that the subjects with Aβ deposits in their brains had, in addition, intense deposits in their cerebral blood vessels—a bleeding-risk condition called cerebral amyloid angiopathy.

Aside from the direct public health implications, scientists will want to know more in general about how Aβ aggregates spread. A first experiment would be to confirm that the Aβ aggregates from cadaver-HGH or the brains of Collinge’s autopsy subjects really can transmit Aβ pathology.

“I think what is important now is to inoculate the extracts into mice,” said Mathias Jucker, a researcher at the Hertie Institute of Clinical Brain Research and German Center of Neurodegenerative Diseases in Tübingen who has pioneered animal-to-animal transmission experiments with Aβ. “The latter are extremely sensitive bioassays and the inoculation will be important since the Aβ seeds in the extracts might be under the level of detection by conventional means. These experiments will take a long time but will show whether there is prion-like transmission.”

There is so far no evidence from epidemiological studies that Alzheimer’s can spread from person to person through casual contact, body fluids, medical blood products, or other medical treatments or procedures. Even CJD, as Collinge emphasized, is transmissible only in special circumstances.

The absence of epidemiological evidence for Alzheimer’s transmissibility isn’t as comforting as it might be, though—because the apparently decades-long lag between Aβ exposure and extensive Aβ pathology would make any association between the two hard to detect.

In particular, scientists may look more closely than they have already at the possibility of transmission, however unlikely, via blood. In the cases just reported, cadaver-HGH was injected into patients’ muscles, so any Aβ aggregates that reached the brain may have done so via the bloodstream—as has been shown possible in animal experiments. (Blood products in the USA and Europe currently are not screened for Aβ aggregates, or even for CJD-causing PrP aggregates.) Although Aβ aggregates have been assumed to be less tough and sterilization-proof than PrP prions—which notoriously resist steam-heating and strong detergents—Jucker and colleagues have found evidence in several studies that Aβ aggregates may be even hardier.

In the latest of these studies, which coincidentally appears this week in Nature Neuroscience, Jucker and colleagues found that Aβ aggregates injected into the brains of mice (which otherwise lacked Aβ to fuel any spread of the aggregates) could be recovered from the mice’s brains six months later and used to seed Aβ pathology in other mice.