Authors: Lauren Pulling
In this latest instalment of our ‘Ask the Experts’ column, we ask the question, ‘Is Alzheimer’s disease transmissible?’. This highly provocative topic has hit the headlines in recent months, so we have drawn together experts from the fields of Alzheimer’s and prion research to share their views on the subject. Our experts this month are Karl Frontzek (University of Zurich, Switzerland), Herbert Budka (University of Zurich, Switzerland), Marc Diamond (University of Texas Southwestern, TX, USA), Masahito Yamada (Kanazawa University, Japan) and Dennis Selkoe (Harvard Institutes of Medicine, MA, USA). Find out more about our experts at the bottom of this page.
Over the coming days, our experts will discuss what is really meant by ‘transmissible’ in a neurological sense, the evidence for and against the case for Alzheimer’s transmission, and how the future of Alzheimer’s research and treatment will be shaped by recent research advances.
What is the definition of ‘transmissible’ in a neurological sense?
KF: To me, a transmissible disease is defined by spread of the agent from one organism to another, be it directly (bodily fluids, aerosols) or via vectors (infusions, medical instruments). When it comes to research about transmissible diseases, in my opinion, it is only a ‘transmissible’ disease if the recipient would not have caught the disease on a natural course, meaning that if one infects an organism with a toxic agent that would develop naturally on its own (e.g., through genetic overexpression or pathological mutation) it is not per sé transmissible.
HB: In a neurological sense, transmission is the consistent elicitation of a disease by inoculation with material from another individual with this disease.
However, the term transmission has been used, sometimes confusingly, for several distinct processes that, in my opinion, need to be distinguished:
- Molecular seeding or templating – a molecule seeds the replication of itself in template-like fashion
- Cell-to-cell spread – propagation of molecules or subcellular structures from one cell to another, e.g., by exosomes or tunneling nanotubes
- Interindividual transmission / infection – from one host to another by an infectious agent, e.g., by bacteria, fungi, viruses, prions. All of these run with a complete infectious cycle (with step-wise infection of, multiplication and propagation within intermediate cell populations, e.g., after oral inoculation). This process may or may not associate with manifest disease.
What neurological diseases are we currently aware of as being transmissible?
KF: On the one hand, you have the textbook infectious diseases such as HIV encephalitis, toxoplasmosis etc. encompassing a broad spectrum of bacterial, viral or parasitic infections that are transmissible. On the other hand, prion diseases, inexorably fatal diseases of the CNS, are defined by the seeded propagation of the pathological, ‘scrapie’ conformer PrPSc onto its cellular counterpart PrPC. They have been known to be transmissible since the pivotal experiments of Carleton Gajdusek and colleagues when they inoculated primates with human prions. They have further gained broad medial attention during the bovine spongiform encephalitis (BSE) crisis at the end of the 20th and beginning of the 21st century. In some countries such as Japan, cadaveric dural grafts contaminated with prions from Creutzfeldt-Jakob Disease (CJD) patients were used during neurosurgical procedures and have led to several hundred iatrogenic CJD cases.
How big an issue are transmissible neurological disorders?
HB: Rather big, as all of these disorders mean significant morbidity and final lethality.
KF: Quite a big one. In terms of known infectious and transmissible agents, such as HIV or prions, we mostly know the procedures to get rid of infectivity when, for instance, an infected patient has been operated on and the medical instruments have to be inactivated for further surgeries etc. Public health measures, such as rapid quarantine of blood products from post-hoc diagnosed, infected patients and constraints for chow supplements, help to reduce spreading infections of known agents.
Frighteningly, on the other hand, there are cases like the Swiss Federal government that has recently cut down its spending on the National Surveillance Centre for Prion Diseases, University Hospital Zurich (Switzerland). Since 2016, only patients with blood donations and suspected CJD or clinical suspicion of the new-variant disease are being transferred for autopsy evaluation. Scientifically, a distinction between new-variant or sporadic CJD can only be made on autopsy, making Switzerland the first industrialized country to almost completely shut down its national prion surveillance system – on the bases of very irrational arguments.
In your opinion, is Alzheimer’s disease (AD) capable of being transmitted?
MD: Yes, but probably only under extraordinary circumstances that are unlikely to occur in practice.
MY: Probably yes. So far, it has been established by many studies that AD-type pathologies (amyloid-beta and tau depositions) are transmissible in experimental settings. In clinical settings, however, there has been no evidence that I am aware of for transmission of clinical AD, although recent studies, including ours, have suggested transmission of amyloid-beta pathology in patients with iatrogenic CJD associated with human growth hormone injection or cadaveric dura mater grafting [1–4]. I consider that AD is ‘capable’ of being transmitted under unusual conditions, as in the transmission experiments. On the other hand, in usual clinical situations, simple transmission of AD would be difficult to occur. However, further study is required into the medical procedures or other events with seeding effects on amyloid-beta or tau aggregation that may facilitate AD pathology, contributing to development of AD.
KF: Sure. Initial work on prion protein seeding and propagation have diverged from the initial theory of Stanley Prusiner, who proposed that the pathological ‘scrapie’ prion conformer would superimpose its pathological conformation onto the nondisease-associated, cellular prion protein. Moreover, one assumes a kinetic model, in which pathological prion protein seeds grow along fibrils that eventually break apart, leading to new pathological seeds . Protein misfolding diseases, be it prion disease, AD or Parkinson’s disease, share ubiquitous protein aggregates that spread along different neuronal routes.
Interestingly, around 25 years ago AD researchers proposed staging schemes for tau pathology (still used in diagnostic neuropathology) that defined tau spread amongst confined routes – recently, cell-to-cell spread was impressively demonstrated for alpha-synuclein in Parkinson’s. I do, however, think that one has to be cautious in regard to the fact that you cannot ‘catch’ AD and we need to understand the routes of propagation before giving sound advice to clinicians and epidemiologists.
DS: Personally, I do not think AD is transmissible in any common meaning of the word. We have no evidence to date that the neuropathological and clinical syndrome of AD per se has really been transmitted from one person to another, but more research on this possibility should be conducted. Prion encephalopathies like Kuru and variant CJD are the only chronic human brain diseases that have been proven to be transmitted from human to human, but even in that example, the large majority of prion diseases (e.g., idiopathic CJD, GSS) do not involve person-to-person transmission but occur sporadically.
- Juanmuktane Z, Mead S, Ellis M et al. Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature 525, 247–250 (2015).
- Frontzek K, Lutz MI, Aguzzi A, Kovacs GG, Budka H. Amyloid-β pathology and cerebral amyloid angiopathy are frequent in iatrogenic Creutzfeldt-Jakob disease after dural grafting. Swiss Med Wkly. 146 (2016).
- Kovacs GG et al. Dura mater is a potential source of Aβ seeds. Acta Neuropathol. 131(6), 911–923 (2016).
- Hamaguchi T et al. Significant association of cadaveric dura mater grafting with subpial Aβ deposition and meningeal amyloid angiopathy. Acta Neuropathol. [Epub ahead of print] (2016).
- Knowles TP, Waudby CA, Devlin Gl et al. An analytical solution to the kinetics of breakable filament assembly. Science 326(5959), 1533–1537 (2009).
Click here to read Part 2: Transmissible Alzheimer’s disease, where our experts discuss questions including:
What current evidence is there for Alzheimer’s disease being a transmissible disease? How could it be transmitted?
You can now also read Part 3: Ethical concerns and future outlook here, where our experts will consider questions such as:
Do we need to address clinical practices in light of the suggestion that amyloid proteins are transmissible?
Karl Frontzek – University of Zurich, Switzerland
Karl Frontzek did his medical studies at the University of Goettingen (Germany) and the University of Newcastle (UK) and obtained his MD from the University of Basel (Switzerland). He is currently doing his residency and MD/PhD in Neuropathology at the University of Zurich (Switzerland). His research is focused on the mechanisms of prion disease. His paper about possible beta-amyloid transmission from dura mater grafts early in 2016 received broad attention with media coverage in Nature, The Scientific American and other journals.
Herbert Budka – University of Zurich, Switzerland
Herbert Budka obtained an MD degree from the University of Vienna, Austria, and there became Professor of Neuropathology. His postdoctoral training included clinical neurology and psychiatry, but his work in scientific research, teaching and medical service is in neuropathology. He retired in 2011 as Director of the Institute of Neurology (Obersteiner Institute) of the Medical University of Vienna, and is currently Senior Neuropathology Consultant at the University Hospital Zurich, Switzerland. His main research interests are neurodegenerative disorders including prion diseases, virus diseases of the nervous system, nervous system tumors and neuropathological characterization of peculiar types of neurological diseases. He was President of the International Society of Neuropathology from 2010 to 2014.
Marc Diamond – Director of the Center for Alzheimer’s and Neurodegenerative Diseases, University of Texas Southwestern, TX, USA
Marc Diamond is the founding Director of the Center for Alzheimer’s and Neurodegenerative Diseases and is a Professor of Neurology and Neurotherapeutics. His research focuses on molecular mechanisms of neurodegeneration in Alzheimer’s disease and related disorders, with the goal of developing novel therapies and diagnostic tools. A therapeutic antibody he co-developed at Washington University in St. Louis (MO, USA) is now entering clinical trials for treatment of dementia. The Center for Alzheimer’s and Neurodegenerative Diseases is comprised of a multidisciplinary group of investigators who are focused on understanding the basis of progressive protein aggregation in human disease. They are using this knowledge to hasten the day when neurodegeneration can be detected presymptomatically and stopped before it causes disability.
Masahito Yamada – Professor in the Department of Neurology and Neurobiology of Aging, Kanazawa University, Japan
Dr Masahito Yamada, MD, PhD, is Professor and Chair in the Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, and Director of Neurological Clinic, Kanazawa University Hospital, Kanazawa, Japan. Dr Yamada graduated from Tokyo Medical and Dental University School of Medicine (Japan) in 1980 and had training in neurology, pathology and neuroscience in Tokyo Medical and Dental University, its affiliated hospitals and the University of California at San Diego (CA, USA). He became Associate Professor of Neurology at Tokyo Medical and Dental University in 1999 and Professor of Neurology at Kanazawa University School of Medicine in 2000. His clinical and research interest is in (1) the brain aging, dementia and amyloid (Alzheimer’s disease, cerebral amyloid angiopathy, etc.) and (2) infection and immunity of the nervous system (prion diseases, etc.). He has been the Chair of Research Committees on Amyloidosis (2005–2011) and on Prion Diseases and Slow Virus Infection (2011–present) by the Ministry of Health, Labour and Welfare, Japan. He is also the Chair of Dementia Section in the Japanese Society of Neurology.
Dennis Selkoe – Vincent and Stella Coates Professor of Neurologic Diseases, Harvard Medical School; Director, Ann Romney Center for Neurologic Disease, Brigham and Women’s Hospital (Boston, MA, USA)
Dr Selkoe obtained his bachelor’s degree at Columbia University (NY, USA) and his Doctor of Medicine at the University of Virginia (VA, USA). He then studied basic neuroscience at the National Institutes of Health (NINDS) and at Harvard Medical School, and trained as a neurologist in the Harvard Longwood Program. Dr Selkoe established an independent laboratory researching Alzheimer’s disease and related basic biological questions in 1978. He advanced through the faculty ranks at Harvard Medical School to become Professor of Neurology in 1990. In 2000, he was named the Vincent and Stella Coates Professor of Neurologic Diseases.
Dr Selkoe enjoys an international reputation as a leading researcher on the molecular basis of Alzheimer’s disease and Parkinson’s disease. His many scientific articles in Nature, Science, Neuron, the Journal of Biological Chemistry and elsewhere have helped lead the field toward novel therapeutics, some of which are in advanced clinical trials. Dr Selkoe was the principal founding scientist of Athena Neurosciences (later part of Elan Pharmaceuticals) and is a founding director of Prothena Biosciences. Among numerous honors, he received the first Metropolitan Life Foundation Award, the Potamkin Prize (American Academy of Neurology), the AH Heineken Prize for Medicine (The Netherlands) and the Pioneer Award and the Lifetime Achievement Award (Alzheimer’s Association). He is a Fellow of the American Association for the Advancement of Science and the American Academy of Neurology, and a member of the National Academy of Medicine (USA).