Alzheimer's beta-amyloid and tau
Alzheimer's, beta-amyloid and tau: research continues

The culprits: beta-amyloid and tau

Alzheimer’s Disease has been blamed on the build-up of two particularly nasty proteins in the brain: beta-amyloid and tau.

Amyloid accumulates in plaques outside neurons, while tau twists into tangles inside. These are the characteristic plaques and tangles seen in the post-mortem Alzheimer’s brain. Patients may still function reasonably well with large amyloid deposits, but life’s curtain is certainly falling once the tendrils of tau take hold. By then the patient is not just losing his keys, but forgetting what they’re called, or even how to use them.

What makes tau so toxic, and what’s it doing there in the first place?

Answering these questions may unlock the riddle of one of humanity’s most devastating afflictions.

What is tau?

Tau in its normal, healthy form helps assemble and maintain the outer structure of neurons. When tau misfolds, it becomes toxic and triggers more tau to misfold, which creates a lethal cascade. The result is the useless debris of tangled tau, like the twisted skeleton of a collapsed building.

Cryogenic electron microscopy can now visualise this damage and finds it in the similar but separate diseases of Alzheimer’s, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and chronic traumatic encephalopathy – each with tau in a different shape. Like Tolstoy’s unhappy families, it seems that tau in healthy brains is all alike, but each disease tangles tau in its own way. Alas this level of detail is only available post-mortem, so the timeline and nature of tau gone rogue remains obscure.

Mitigating the plaques and tangles

Various efforts to target and remove plaques and tangles have also had disappointing results. Promising strides have at least been made in imaging techniques that permit early detection of the disease.

Notable here is a form of positron-emission tomography, Tau PET, which can at least offer patients a reliable diagnosis and prognosis.

Neurocentrix uses this imaging in research and hopefully it will soon be available for clinical use.

Future techniques using antibody fragments that bind to tau are being investigated. Meanwhile over 20 tau-specific drugs are being evaluated in clinical trials. These promise to slow and dampen Alzheimer’s symptoms, but a cure will remain elusive until we understand why amyloid and tau form in the first place.

One intriguing idea has always lurked around the margins of research. A trail of tantalising clues has even brought it to the level of genuine hypothesis.

This is the idea that Alzheimer’s disease is inflammatory, akin to asthma or rheumatoid arthritis. By this thinking, the brain in Alzheimer’s is not merely crumbling with the march of time, but like a building suddenly engulfed by fire. The blaze is the brain’s own defences gone haywire; the plaques and tangles, the smouldering ruins.

The clues and further research

The first clue comes from the influenza pandemic that followed World War I. Researchers observed a curious anomaly among the survivors: increased rates of Alzheimer’s and Parkinson’s disease. Something about the virus primed the brain for dementia! Yet that made little sense since decades had passed with no signs of brain damage, and the virus was long gone. Unless the virus left something behind … something in the immune system.

A possible explanation was the virus sharing a structural similarity with a brain protein produced in old age, perhaps even amyloid or tau itself. Once these proteins formed naturally, the immune system found a match and started forming antibodies. A devastating inflammatory cascade, lurking dormant for decades, was set in motion. Meanwhile people who escaped the virus never formed the same antibodies, and so were less likely to develop those dementias.

Further evidence comes from the fact that key dementia proteins are in fact part of the immune system.

Alpha-synuclein of Parkinson’s, and amyloid of Alzheimer’s, are both antimicrobials. Both could therefore be part of a misplaced inflammatory response. Perhaps a pathogen triggers this, as in the influenza epidemic, or more disturbingly it could be from regular clearing of cellular debris. Here the immune system mistakes a harmless protein as an invader and sets off an inflammatory response which just happens to cross-react with something in the brain. Imagine the office cleaner has instructions to recycle all the old photocopy paper. She sets about her task with alacrity, but mistakes loose paper on desks as part of her remit. Off to recycling they go too. But then she gets carried away and starts tearing pages out of the files to recycle as well. After a few weeks, the losses are affecting productivity, and after a few months the office can barely function at all.

For overzealous cleaning to be the reason why some people get Alzheimer’s and others do not, there must some genetic link, and this is precisely what researchers have found. Almost all genes tied to Alzheimer’s are involved in cellular clearing. The unfortunate crossover comes from the dual function of the brain’s auxiliary cells, which are not just vital for supporting neurons but are also actively involved in immune processes. With cleaning and cognitive functions so tightly woven, the brain is exquisitely vulnerable if its supporting cells go awry.

On the brighter side, if the protein similarity is not present and the inflammatory cascade never occurs, then Alzheimer’s may be avoided. Here amyloid and tau appear but never trigger the immune system. In this scenario, we would find patients that have extensive deposits of these proteins but few symptoms, and this is precisely one of the paradoxes researchers have discovered.

A recent study in rodents showed that priming with inflammation massively ramped up the damage to neurons. Researchers have also noticed that people regularly taking anti-inflammatory drugs (e.g. ibuprofen) developed dementia one to two years later than average.

The major argument against an inflammatory view of Alzheimer’s is that an immune trigger could occur at any time throughout life, and Alzheimer’s is found almost exclusively among the elderly.

A possible reply is the analogy of arthritis, which is both an inflammatory process and more common with advancing age.

The paradox is explained by accumulating wear and tear making the inflammatory cascade more likely. The same may be true in the brain, whereby debris naturally accumulating with age becomes increasingly likely to harbour a piece that the immune system will identify as hostile. Susceptible individuals carry a long-dormant immune response from a virus, gut microbe, or genetic flaw, and only after a specific tipping point does it reveal itself.

Compelling as these reasons may be, the inflammatory cascade they imply remains speculative and unproven, and the hypothetical spark unknown.

In fact, many culprit sparks are likely because a single spark would probably have been noticed already. After all, we found that smoking causes lung cancer long ago, but understanding precisely why remains elusive.

Future treatments for Alzheimer’s are likely to involve anti-inflammatory measures, and eventually a cure may come from targeting the precise pathway. Until then, we can expect that an improved understanding of brain inflammation will lead to blood tests that better predict the onset and prognosis of Alzheimer’s.

And at least the hunt for a cure has some leads at last.

Further reading

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