The older we get, the more that housekeeping can feel like a burdensome chore. Our brain has the same problem – it has a self-cleaning system which nightly flushes out toxic substances that build up inside it throughout the day.
But as we age that cleaning mechanism, called the glymphatic system, becomes ever less efficient.
Now a growing band of scientists is convinced that this waste-disposal failure is the fundamental culprit behind two devastating neurological diseases: Alzheimer’s and Parkinson’s.
What’s more, they believe that boosting the system could produce effective cures for these lethal conditions by clearing out proteins that can otherwise build up, destroying brain cells. These proteins are amyloid-beta in Alzheimer’s, and alpha-synuclein in Parkinson’s.
This new approach seems more crucial than ever, now that drugs hailed as ‘breakthroughs’ for Alzheimer’s because they can remove these proteins have controversially just been declared practically ineffective.
Earlier this month experts at the Cochrane Collaboration published their analysis of data from 17 studies of these drugs – which include donanemab and lecanemab – concluding that they ‘make no meaningful difference’.
This follows the decision last year by the National Institute of Health and Care Excellence (NICE) not to approve their use in the NHS because of their limited effect, high cost and potential side-effects include brain swelling.
But could boosting the brain’s self-cleaning mechanism offer an effective alternative?
Research published in the Journal of Alzheimer’s Disease in 2019 found that patients with dementia spent much more time sleeping on their backs compared with healthy people – so the position we sleep in may have a significant influence
Only discovered in 2012 at the University of Rochester, New York, the glymphatic system moves fluid around the brain to flush out waste. It is believed to work most effectively at night at the times when the brain is in its deepest, most restful sleep.
To find an effective booster for the glymphatic system quickly, researchers are trying to identify existing drugs that are proven safe in humans which might also have this beneficial effect.
One candidate is dexmedetomidine, an anaesthetic used in surgery where patients remain conscious.
Last year researchers in China trialled dexmedetomidine in mice and found that low doses increased the activity of the glymphatic system, and significantly reduced levels of brain inflammation caused by a build-up of the rogue proteins, reported the journal American Chemical Society Nano. (They chose dexmedetomidine as it can put the brain into its deepest form of slumber.)
Then, in March, US scientists claimed to have shown that dexmedetomidine can work similarly in humans – using it in combination with midodrine, a drug that raises low blood pressure, which may help boost fluid flow in the brain.
This combination increased glymphatic-system activity by around 10 per cent – and in turn increased the rate at which patients’ brains removed the rogue proteins.
Meanwhile, strengthening the glymphatic system also appears to offer hope for Parkinson’s disease.
Current treatments can only help to minimise symptoms, and become less effective over time. This month, researchers in Australia claimed to have discovered that a drug already approved for humans can boost glymphatic cleansing and reduce levels of toxic proteins in the brains of those with Parkinson’s.
Zhao Yan, a scientist at Swinburne University of Technology in Melbourne, told the Oxford Glymphatic and Brain Clearance Symposium that a drug – dubbed compound X – has shown dramatic results in mice with Parkinson’s, improving balance and mobility in 80 per cent of subjects. They hope to begin trials in people within the next year.
One of the UK’s leading researchers in the glymphatic system, Ian Harrison, a principal research fellow at University College London, told the Mail that the main channel of the glymphatic system, which enables fluid to flow in and out of the brain, is called Aquaporin-4.
When this is blocked in animals with Alzheimer’s and Parkinson’s, ‘they quickly show symptoms of these diseases’, he says.
‘When you experimentally inhibit the glymphatic system you see more build-up of amyloid-beta in the brain. This disrupts communication between brain cells and is implicated in Alzheimer’s,’ he explains.
In Parkinson’s, studies show there is a build-up of abnormal alpha-synuclein in the brain.
Ian Harrison is a principal research fellow at University College London
Ian Harrison explains: ‘This attacks cells in the mid-brain that produce dopamine [a chemical messenger that regulates movement] – and it is a lack of dopamine that causes the neurological symptoms of Parkinson’s.
‘We are now finding drugs that can speed up the function of the Aquaporin-4 channel, so that hopefully we can stop the toxic build-up in the first place.’
One of the key features of the glymphatic system is that it is thought to be more active during deep sleep. Ian Harrison’s team is also testing novel drugs to improve the quality of people’s sleep – in the hope that this will strengthen their glymphatic system. As he explains: ‘Ordinary sleeping pills don’t work. They increase sleep duration but not the quality of sleep, whereas the glymphatic system works during the deepest forms of sleep, known as non-REM and slow-wave sleep.’
Another approach is surgery. As the Mail recently reported, keyhole surgery is being used in China to treat Alzheimer’s, with claims it can improve cognitive and physical health.
The surgical technique was developed to treat lymphoedema – swelling of the arms and legs due to a build-up of fluid as a result of lymph nodes being removed.
In the procedure, lymphatic vessels, which drain from the nodes, are connected instead to neighbouring veins – in dementia, this is done in the neck to ‘unblock’ the dysfunctional glymphatic flow, enhancing the removal of the damaging proteins.
Lifestyle changes may help our glymphatic systems, too. ‘Decent duration and quality of sleep appear to be particularly important,’ says Ian Harrison.
The position we sleep in may also have a significant influence, according to a US study in the Journal of Neuroscience in 2015. In studies on rats, researchers found that their natural sleeping position, curled up on their right sides, allows for optimum brain-waste removal, and particularly more so than sleeping on their backs or stomachs.
Meanwhile, research published in the Journal of Alzheimer’s Disease in 2019 found that patients with dementia spent much more time sleeping on their backs compared with healthy people.
Exercise can also support a healthy glymphatic system. Ian Harrison says: ‘Mice given free access to running wheels show far higher activity in their glymphatic systems. This is to do with improved fluid flow in the brain.’
Last year, a study in Nature Communications found a similar benefit in humans. MRI scans of healthy volunteers who undertook three months of daily training on exercise bikes reported that their brains showed significantly improved glymphatic efficiency and less evidence of harmful inflammation.
A Mediterranean diet – with plenty of vegetables, fruit, wholegrains, beans, nuts, fish and olive oil – may also increase glymphatic activity, because they are rich in antioxidants, omega 3s, vitamins, zinc and magnesium, reported the journal Critical Reviews in Food Science and Nutrition earlier this month.
These nutrients together may boost the activity of the Aquaporin-4 channel, as well as reducing brain inflammation and fostering deep sleep. By contrast, the researchers warned that high-fat diets and excessive alcohol intake are associated with reduced Aquaporin-4 activity.
But not all scientists are convinced that boosting the glymphatic system will prevent Alzheimer’s and Parkinson’s.
Professor Bart De Strooper, founder of the UK Dementia Research Institute at University College London, says: ‘The glymphatic system is an exciting area of research, but it is still far from settled science.
‘Most of the evidence so far comes from mouse studies. We should be careful not to overstate what we know, especially when it comes to the human brain, which is vastly larger and more complex than a mouse brain.’
He adds that while ‘the link between sleep and brain clearance is appealing, it remains scientifically controversial’.
Robert Howard, a professor of old-age psychiatry at University College London, is more emphatic: ‘There are absolutely no data to convincingly support the idea that the glymphatic system, or its failure, are somehow linked to risk for Alzheimer’s.’
Professor De Strooper concludes: ‘This is a promising research direction, but at best it might become part of a broader strategy to slow disease.
‘We are still at the stage of trying to understand the plumbing, not yet at the stage of prescribing the repair.’
