From Seed to Signature: Is amyloid pathology capable of 'seeding' in humans?

Alzheimer’s disease - A term we hear more and more often in our ever-ageing population. The memory-stealing, personality-altering condition affects millions of people across the globe mainly in the later stages of life and although the condition is common, we still do not know what causes Alzheimer’s in over 99% of cases. Could the disease be caused by lifestyle choices? Could we warn of neurodegeneration if we smoke less and exercise more? What about susceptibilities in an individual's personal genetic code? Could one mutated gene trigger a cascade of untoward events in the brain? Another much scarier mechanism flung around the news recently was Alzheimer’s could potentially be ‘transmitted’ - a word nobody wants to hear when linked with a currently incurable disease.

‘Contagious’ Neurodegeneration: Prion Diseases

I have been asked several times by people curious in my work if it is possible to ‘catch’ Alzheimer’s disease. And my response has always been a firm no as there have been no reported cases of human-to-human transmission (passing) of Alzheimer’s. However, there is a rare class of neurodegenerative conditions which can be transmitted called Prion diseases. Such diseases are caused by Prions; an abnormal variant of a protein found on the surface of every neuron in a healthy mammalian brain. Unlike a typical virus which injects its unwanted DNA into human cells in order to replicate, rogue prions are able to transform normal prion proteins into fellow rogue prions by altering their shape. This allows the rogue prions to spread throughout the brain, which leads to widespread neuron death and brain tissue loss.

Contracting a prion disease is much rarer than the catching a virus through a cough or splutter as transmission is thought to require direct ingestion, injection or insertion of the rogue prion into an individual. A famous case of prion disease was the BSE crisis in the 1980s/1990s; where almost 200 individuals in the UK died of a prion disease called variant Creutzfeldt Jakob Disease (CJD) after eating beef contaminated with cattle prions. Another incidence of prion transmission came from young individuals of short-stature being injected with inadequately-purified growth hormone isolated from the pituitary glands of cadavers, failing to remove all rogue prions and leading to cases of iatrogenic CJD (iCJD). Also, it has been noted abnormal prions can stick to metal neurosurgical tools, meaning extensive sterilisation must be undertaken following brain surgery. In spite of prion diseases hitting headlines for their infectious nature, there are an array of other prion diseases which are not contracted due to transmission. These can occur due to familial inheritance of prion gene mutations or randomly, much like the majority of Alzheimer’s cases.

Research paper: An example of amyloid seeding in humans?

The majority of neurodegenerative diseases are characterised by misfolded protein aggregates in the brain at post-mortem, with Alzheimer’s patients all having misfolded amyloid-beta and tau in their cerebrum. It has been hypothesised that as these pathologies are both formed of misfolded versions of resident brain proteins, they might possess similar properties to prions such as the ability to 'seed' in the brain. Many mouse models have been used to explore this theory over the past decade, with results looking like both rogue proteins can induce pathology following injection. But a real human insight came from the study of the brains of a cohort of patients who had succumbed to iCJD following injection of contaminated growth hormone. Although all patient brain tissue had hallmarks of prion diseases, some of these individuals also had amyloid plaques; the supposed first sign of Alzheimer’s; in the brain and blood vessels. As it is unusual to see amyloid pathology in such young individuals, the hypothesis was formed that the growth hormone vials derived from human pituitary glands were also contaminated with amyloid seeds, which had lead to the formation of amyloid plaques in the brain.

Researchers at University College London (UCL) accessed the exact growth hormone vials used to inoculate patients in the 1950s-1980s and inoculated the material into mice which form amyloid plaques with age. The researchers wanted to test if the growth hormone material would increase the number of amyloid plaques following a set incubation period, which would argue amyloid seeds are present in the growth hormone vial. After an 8 month incubation, the mice injected with material from the suspected amyloid-contaminated vials of growth hormone material did experience an increase the level of amyloid plaques in the brain compared to suspected non-amyloid containing vials, synthetic growth hormone and sham-inoculated controls. These amyloid plaques were also seen deposited in blood vessels; the hallmark of a disease called cerebral amyloid angiopathy (CAA), which can cause vessel blockages and strokes. The study concluded the likely reason for the iCJD patients harbouring amyloid plaques was due to the inoculation of amyloid seeds with the growth hormone preparation, and CAA can now be classified as an iatrogenic disease.

Does this mean Alzheimer’s is transmissible?

While the implications of this study can be stretched by the media, one point is clear: Alzheimers disease was not transmitted in these mice - amyloid was, and we are still unsure of the exact role amyloid plays in the mechanism of neurodegeneration. There are a cohort of healthy older people who die with high levels of amyloid and no signs of Alzheimer’s disease, providing an argument amyloid burden can exist without neuron death. Also, no comments were made on other features necessary to diagnose Alzheimer’s in these mice, such as tau pathology and neuron death; with the former also not being noted in the iCJD patients.

But could these individual’s brains have gone on to develop early Alzheimer’s disease if iCJD hadn’t taken hold? Confirming this theory would require a case of a growth hormone-treated individual with Alzheimer’s disease, none of which have obviously presented yet. What this study does highlight is amyloid is potentially able to seed in humans, therefore the need to fully comply with approved sterilisation techniques for neurosurgical tools to ensure the removal of prions and amyloid is of the upmost importance.

Alzheimer’s disease still cannot be described as infectious akin to prion disease or transmissible, but this study hints amyloid pathology could be seeded in humans under extremely rare circumstances which should not arise any more due to safety procedures. And what this means for contracting the disease is still unclear as the mechanism of Alzheimer’s disease are still under investigation.

What did you think of this study? Let me know on my social media pages!




Paper: Purro et al (2018). Transmission of amyloid-β protein pathology from cadaveric pituitary growth hormone. Nature 564, 415-419

For some sciencey reads on this topic, click the links below

A scientific review of Prion diseases

Neurodegenerative diseases: expanding the prion concept

Amyloid beta as a Prion: Review

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