Experts discuss knowledge gaps on potential risks for researchers working with Alzheimer’s disease samples
An international group of scientists and experts convened by NIA write that there are no clinical data or evidence to suggest Alzheimer’s disease is infectious, like a cold or the flu. However, research is emerging that the hallmarks of the disease — proteins like amyloid and tau — can act as agents of transmission in experimental systems, and data is limited on the implications for those working and conducting experiments with Alzheimer’s tissue and other samples. Authors representing three U.S. federal health agencies, including NIA, and more than a dozen other research organizations from Germany, the U.K., and the U.S., summarized the workshop in the October 1, 2020 issue of the Journal of Neuropathology and Experimental Neurology.
“Taking a thoughtful look at the most recent available scientific data and literature, the research community has identified some key questions,” said Eliezer Masliah, M.D., director, Division of Neuroscience, NIA. “While we see no signs that neurodegenerative diseases like Alzheimer’s are infectious in the classical sense, the question of transmissibility is important, and we certainly want to make sure neuropathologists and those working in neurodegenerative diseases such as Alzheimer’s are safe.”
Neuropathologists, specialists in brain and nervous system diseases, handle autopsy and biopsy samples, for example, examining brain tissue under a microscope. They routinely use standard laboratory safety techniques and personal protective equipment (PPE), such as gloves and eye protection. Research has been emerging in the past few years raising the possibility that neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Lewy body dementia, multiple system atrophy, and frontotemporal dementia, share characteristics with prion diseases, such as Creutzfeldt-Jakob Disease. The authors, which included representatives from the Centers for Disease Control and Prevention, Food and Drug Administration, and NIA, note that neuropathologists and those working with known prion diseases have specific, extra procedures for handling animal models, cell culture systems, tissue (both human and animal), and biological fluids. But there are no comparable guidelines for neurodegenerative disorders such as Alzheimer’s and related dementias.
The researchers discussed at the workshop, and present in the paper, limitations of current knowledge of transmissibility of other neurodegenerative diseases (Alzheimer’s and related dementias), as well as areas that may require further research to guide tissue-handling practices. They focused on how experimental activities, including storing and sharing tissue samples, could carry with them risk of transmission and ask how to meet the goal of managing and minimizing that risk.
“We in the research community have been working with many of these proteins for decades and know they’re not infectious like a virus, yet we’re seeing more clearly now how they have a transmissibility feature in experimental settings,” said Masliah. “The questions that the paper says are important to answer are what extent might there be transmissibility risk for researchers — not in routine life — but when they do scientific tests. For example, are neuropathologists wearing the appropriate PPE when handling Alzheimer’s samples?”
The evidence emerging to date on transmissibility is primarily in experimental systems, i.e., cell and animal models. That research appears convincing and consistent that some neurodegenerative disease proteins have prion-like behavior. Those proteins include amyloid and tau, which are associated with Alzheimer’s; alpha-synuclein, which is linked to Parkinson’s disease and Lewy body dementia; and tau and TDP43, which are associated with frontotemporal dementia. The authors noted five characteristics that would suggest a protein is acting like a prion. A key “prion-like behavior” is evidence that a protein could misfold in a way that forms a protopathic seed. This is the ability of an abnormal protein associated with a disease to cause more of that same abnormal protein in another host, animal, cell, or person. The authors discussed how amyloid seeds from a human Alzheimer’s disease sample injected into a mouse leads to development of plaques. They also note neuron-to-neuron transmission of tau in cell and mouse models. And they cited evidence in animal models of how misfolded alpha-synuclein can be transmitted across brain systems.
“This is an example of science working at its best — how questions get asked and research builds to both provide answers and ask more questions,” explains Nina Silverberg, Ph.D., director of the NIA Alzheimer’s Diseases Research Centers program, and a co-author of the paper. “Seeing what started as a handful of papers on the topic of transmissibility, then discussing in the Alzheimer’s centers, we decided to take a closer, collaborative look, which led to this workshop and paper. Now, we look forward to further work to improve our understanding and help assure that researchers remain safe.”
The authors note that a similar exercise happened in Europe with discussion focusing more closely on clinical settings and broader public health concerns. Acknowledging the European group (whose paper appeared online in Lancet Neurology, September 16, 2020), the researchers emphasized that studies looking more closely, with international collaboration specifically at transmissibility concerns, such as protopathic seeds and how they may persist, will help settle questions of risk both in the research community and potentially in clinical settings.
The workshop was funded by the NIA Division of Neuroscience.
Reference: Asher DM, et al. Risk of transmissibility from neurodegenerative disease-associated proteins: Experimental knowns and unknowns. Journal of Neuropathology and Experimental Neurology. doi: 10.1093/jnen/nlaa109.