Evidence for Person-to-Person Transmission of Alzheimer's Pathology
Study raises question about whether proteins implicated in the disease are capable of spreading through medical procedures
Prions are the misshapen proteins that replicate by inducing normal proteins to misfold and aggregate in the brain, leading to rare diseases such as mad cow and kuru. In recent years, scientists have discovered that similar processes of protein misfoldingare at work in many neurodegenerative disorders, including Alzheimer’s, Parkinson’s and Lou Gehrig’s disease. Now, a study in Nature reveals the first evidence for human-to-human transmission of the misfolded proteins that underlie the pathology of Alzheimer’s disease.
The new findings draw upon earlier research conducted on a prion disease. Between 1958 and 1985, a number of individuals with short stature received shots of human growth hormone extracted from the pituitary glands of cadavers. The gland is a pea-sized structure that sits at the base of the brain. Some of these samples were contaminated with prions that caused certain patients to develop Creutzfeldt-Jakob disease (CJD), a rare and fatal brain disorder. Treatments ceased once these reports came to light, but by that time an estimated 30,000 people had already received the injections. As of 2012, researchers have identified 450 cases of CJD worldwide that are the result of these growth hormone injections and other medical procedures, including neurosurgery and transplants.
Misfolding of the amyloid-beta proteins is a hallmark of Alzheimer’s. Previous studies have shown that minute amounts of amyloid-beta injected into animals such as mice or monkeys act as seeds that initiate a chain reaction of protein misfolding that resembles the pathology of Alzheimer’s. However, until now, no studies have found evidence that this process occurs in humans.
To explore the question of human transmission, John Collinge, a neuroscientist at University College London and his colleagues, conducted an autopsy study of eight patients who died from CJD after treatment with cadaver-derived growth factor. To their surprise, they found that six of the brains had the amyloid-beta pathology found in Alzheimer’s patients, and four exhibited some degree of cerebral amyloid angiography, in which amyloid deposits build up on the walls of blood vessels in the brain.
The patients were between the ages of 36 and 51—typically too young to exhibit Alzheimer’s pathology—and none of the individuals bore genetic mutations associated with early onset of the disease. All evidence pointed toward one possibility: Like prions, amyloid-beta seeds were in the growth hormone injections and infected these individuals. Although none of the brains showed any other Alzheimer’s disease markers, such as buildup of another misfolded protein called tau, the researchers suggest that had the patients not died young, they would have developed the disease later in life.
The research may be a first step toward answering the question of whether human-to-human transmission of pathological proteins is possible. “This is an observational study,” Collinge says. “We’re simply describing what we see in these patients and we are trying to explain that.” This study alone, he says, does not suffice to prove that the Alzheimer’s disease process can be induced in one individual through contact with another’s brain tissue. In a follow-up study, the researchers are hoping to obtain archived batches of the cadaver-derived human growth hormone to look for the presence of telltale, small clusters of amyloid-beta.
One prominent Alzheimer’s investigator—John Trojanowski of the University of Pennsylvania, who was not involved in the study—asserted that the research does not provide a clear answer about whether Alzheimer’s pathology can spread between humans. Trojanowski says that the study will “generate more confused thinking and stoke unreasonable concerns by the public about the infectivity of Alzheimer’s, which I think does not help the field of prion and AD research.”
He points to the small size of the study and the fact that the subjects did not show other signs of Alzheimer’s. “Also, studies show that plaques and tangles begin to deposit as early as the second and third decade of life, which means the subjects could merely have aging-related deposition of amyloid-beta.”
But other researchers found the study to be an important contribution to the growing body of research showing that many neurodegenerative diseases may be induced through prionlike processes. All direct evidence of transmission was conducted in animal studies, Collinge says, raising questions about whether the same pathology was present in humans. “The best evidence for the transmissibility of amyloid-beta lesions comes from animal studies, in which various factors are carefully controlled and competing hypotheses are ruled out,” says Lary Walker, a neuroscientist at Emory University not involved in the study. “[This study] adds an important dimension to the establishment of the prion paradigm.”
Collinge emphasized that Alzheimer’s and prion diseases such as CJD cannot be “caught” through direct contact and previous epidemiological studies have found no evidence that a history of blood transfusion is associated with increased risk of Alzheimer’s disease. However, the possibility remains that certain medical procedures, such as transplants and neurosurgery, may expose individuals to amyloid-beta seeds, and the possibility of transmitting them through blood will likely become an avenue of further research.
In another study, published today in Nature Neuroscience, Mathias Jucker from the University of Tübingen in Germany and colleagues, including Lary Walker, found that amyloid-beta seeds have the ability to persist in the brain for months and regain pathogenic properties when introduced to the right environment. Together with the evidence that Alzheimer’s pathology can be transmitted between humans, scientists are starting to look carefully at the ways in which a range of neurodegenerative diseases may develop over the course of decades—and the role that transmission between humans may play. “I think we all agree that more systematic research in this area is necessary,” says Jucker.
*Gary Stix contributed reporting