This latest instalment of our ‘Ask the Experts’ column – with Karl Frontzek (University of Zurich, Switzerland), Herbert Budka (University of Zurich, Switzerland), Marc Diamond (University of Texas Southwestern, TX, USA) and Masahito Yamada (Kanazawa University, Japan) – focuses on the question, ‘Is Alzheimer’s disease transmissible?’. Yesterday we explored the subject of transmissible neurological disorders, and today we focus specifically on the evidence for and against the suggestion that Alzheimer’s disease could be transmissible.
Read Part 1 of the debate here. Find out more about our experts at the bottom of this page.
What current evidence is there for Alzheimer’s disease being a transmissible disease? How could it be transmitted?
MD: Both tau and amyloid-beta fibrils can be inoculated into animals to create disease. There is no evidence that Alzheimer’s disease (AD) is initiated in one individual through exposure to material from another afflicted individual.
“For the past few years scientific data has been accumulating indicating ‘prion-like’ or ‘prionoid’ features of Alzheimer’s disease – both for tau protein and beta-amyloid.”
– Karl Frontzek
KF: AD is defined through its two hallmark misfolded proteins, namely beta-amyloid and tau protein. For the past few years scientific data has been accumulating indicating ‘prion-like’ or ‘prionoid’ features of AD – both for tau protein and beta-amyloid.
Several groups have isolated aggregated beta-amyloid plaques from human AD patients and inoculated them into mice (that unfortunately were in a lot of cases on a genetic AD background making it hard for these studies to claim true prion properties of beta-amyloid or tau since the mice would have developed AD eventually). Nonetheless, what they could see was the de novo or accelerated formation of plaques (for beta-amyloid) or tangles (for tau protein).
In 2015, a study in Nature by Sebastian Brandner (University College London, UK) and colleagues made a big splash about the transmissibility of AD. They investigated the brains from patients receiving growth hormone (GH) preparations that were already known to be contaminated with Creutzfeldt Jakob Disease (CJD) prions. Unexpectedly, they discovered that these GH recipients suffered from AD at a very young age, as well as that beta-amyloid was accumulating in the pituitary glands of AD patients – pituitary glands comprising the source of GH preparations.
At the beginning of this year our lab worked in cooperation with the Medical University of Vienna (Austria) on a study that indicated that in young patients who received CJD-contaminated cadaveric dural grafts, a lot of concomitant AD pathology could be observed  – adding to the observations of Brandner and coworkers.
Gabor Kovacs from the Medical University of Vienna has further analyzed these dural grafted brains  and highlighted a close correlation of dural patches and brain beta-amyloid pathology. Transmission could be achieved through seeded propagation of contaminated dural grafts, growth hormone preparations etc. although more research has to be performed.
How do amyloid-beta proteins, the pathological hallmark of AD, compare functionally to known prion proteins?
MD: There are many similar features. However, beta-amyloids appear to promote extracellular deposition in the brain, without a clear effect on brain function, whereas prion protein clearly afflicts cells and causes neurodegeneration.
HB: Amyloid-beta is only one of two pathological hallmarks of AD (amyloid-beta and tau). Both amyloid-beta and PrPSc (the disease-associated misfolded conformer of the prion protein PrP, as in scrapie (sc), which is the molecular constituent of a prion) are able to seed and propagate molecularly and apparently from cell to cell. However, only PrPSc has shown a complete infectious circle (with step-wise infection of, multiplication and propagation within, intermediate cell populations e.g., after oral inoculation).
In contrast to amyloid-beta, tau has not been shown to propagate in the previously mentioned human tissue studies of amyloid-beta propagation by pituitary extracts  and dural grafting [1, 2] .
Aside from transmission, what other biological explanations could there be for observations that indicate that AD may be infectious, such as those from John Collinge’s lab of amyloid plaques within Creutzfeldt Jakob disease patients ?
MY: Aside from transmission of amyloid-beta pathology, explanations for the observation of significantly more amyloid-beta deposition in patients with iatrogenic CJD, such as growth hormone-associated cases and dura mater graft-associated cases [3, 1, 4], include the possibilities that: 1. abnormal prion protein (PrPSc ) might have promoted amyloid-beta depositions by cross-seeding effects of PrPSc on amyloid-beta, and that 2. amyloid-beta deposition in the brain might be associated with neurosurgery itself that accompanied dura mater grafting – increasing amyloid-beta deposition in the brain after traumatic brain injury has been widely studied in both human and animal models .
“The Collinge study was very provocative, but was not evidence of transmission of Alzheimer’s disease.”
– Marc Diamond
MD: The Collinge study was very provocative, but was not evidence of transmission of AD. The patients died of prion disease, and the supposition was that if they hadn’t that they might have developed AD. That is not known, however.
KF: John Collinge’s observations have shown AD pathology in growth hormone recipients’ brains and accumulation of beta-amyloid in cadaveric pituitary glands – the major source of growth hormone until this treatment was ceased due to spread of iatrogenic CJD. One has to state however, that to my knowledge it was not explicitly tested whether those preparations that were eventually administered to patients were beta-amyloid contaminated. On the other hand neither do I believe that these preparations are utilized anymore or that any pharmaceutical firm would provide these preparations due to liability issues etc. This does not however make Collinge’s and Brandner’s observations unlikely.
The only other observation I am aware of that has indicated possible alternative explanations for transmissibility are the reports discussing beta-amyloid as a reactive product of more general brain damage, just like reactive astrocytes, reactive oxygen species etc. Since individuals have claimed to observe beta-amyloid in multiple sclerosis plaques this could be viable, however this is less substantiated.
HB: There are kuru type amyloid plaques in CJD composed by PrPsc, and there may be additional amyloid-beta plaques in CJD, either by coincidence in an aging individual (in whose brain some degree of amyloid-beta deposition is very frequent), or by some yet unclear molecular connection, such as by ‘cross-seeding’. Such a phenomenon might occur locally, when one sticky amyloid protein aggregates on another of a different molecular composition.
There are also some data on a molecular interplay between amyloid-beta and other neurodegeneration-related proteins including the normal (cellular, anon-amyloid) prion protein PrP, but this interplay is far from well understood.
Is there any evidence to suggest that tau proteins could be transmissible?
“It is critical to emphasize that the vast majority of individuals who develop tauopathy have not had the type of exposure to human tissue that we would expect to be required to transmit disease.”
– Marc Diamond
MD: There is no evidence that tau pathology is transmissible that is directly relevant to human health from an ‘infectious’ standpoint. However, in appropriate experimental models that over-express human tau, the pathology is clearly transmissible. Inoculation of tau into experimental mice has not yet produced clear neurodegeneration, however. Certainly tau inoculation into wild-type mice has not produced disease, although this has been clearly shown by the Virginia Lee laboratory (Center for Neurodegenerative Disease Research, University of Pennsylvania, PA, USA) for alpha-synuclein. In terms of humans, whether tau or other amyloid proteins could account for some small fraction of disease through contaminated instruments, tissue transplants, etc., is not known. It is critical to emphasize that the vast majority of individuals who develop tauopathy have not had the type of exposure to human tissue that we would expect to be required to transmit disease. At this point this is also true for bona fide prionopathy: there are now very few cases of transmitted disease – most arise spontaneously, or due to inherited mutations in the PrP gene.
HB: Like for amyloid-beta, there is also evidence for tau (and other neurodegeneration-related proteins, see ). Ample experimental evidence exists for molecular seeding and self-propagation. Seeding recruitment of normal tau by pathological tau conformers has been shown , fostering speculation of neuron-to-neuron propagation in AD  that could be demonstrated in a model of early AD . Moreover, tau proteins obtained from brain tissue of various tauopathies propagate in cells and mice in distinct fashion suggesting distinct tau strains , another similarity with prions that are known to occur in distinct strains.
- 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).
- Jaunmuktane Z et al. Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature. 525, 247–250 (2015).
- 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).
- Smith DH, Johnson VE, Stewart W. Chronic neuropathologies of single and repetitive TBI: substrates of dementia? Nat. Rev. Neurol. 9(4), 211–221 (2013).
- Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457(7233) 1128–1132.
- Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45–51 (2013).
- Guo JL, Lee VM. Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol. Chem. 286(17), 15317–15331 (2011).
- Braak H, Del Tredici K. The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol. 121(2), 171–181 (2011).
- de Calignon A et al. Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73(4), 685–697 (2012).
- Sanders DW et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82(6), 1271–1288 (2014).
The opinions expressed in this interview are those of the interviewees and do not necessarily reflect those of Neurology Central or Future Science Group.
Catch up on Part 1: Introduction to transmissible neurological disorders
In Part 3: Ethical concerns and future outlook, the panel discuss questions including:
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 (Part 1 contributor) – 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).