Problems
with the brain's waste clearance system could underlie many cases of
dementia and help explain why poor sleep patterns and cardiovascular
risk factors such as high blood pressure increase the risk of dementia.
A study led by researchers at the University of Cambridge found that
impaired movement of cerebrospinal fluid (CSF) – the clear liquid that
cushions and cleans the brain – predicted risk of dementia later in life
among 40,000 adults recruited to the UK Biobank. Their findings are published today in Alzheimer's & Dementia: The Journal of the Alzheimer's Association.
In the healthy brain, the so-called glymphatic system serves to clear
out toxins and waste materials, keeping the brain healthy. Only
discovered as recently as 2012, this system functions by flushing CSF
through the brain along tiny channels around blood vessels known as
perivascular spaces. It collects waste then drains out of the brain,
helping keep it clean and healthy.
The glymphatic system is thought to be important in protecting
against many of the common forms of dementia, which are often
characterised by the build-up of toxic substances in the brain – for
example, Alzheimer's disease sees amyloid 'plaques' and tau 'tangles
accumulate in brain tissue.
One of the most common forms of dementia is vascular dementia, caused
by reduced blood flow to the brain. The most common cause of this type
of dementia is cerebral small vessel disease, which affects the small
blood vessels in the brain. But the impact of cerebral small vessel
disease is even greater because it also interacts with other dementias
making them worse; for example, a study of nuns in the US found that
among those nuns whose brains showed signs of Alzheimer's disease post
mortem, only around a half exhibited symptoms of dementia – but this
increased to around nine in 10 if they also had cerebral small vessel
disease.
Professor Hugh Markus and colleagues at the University of Cambridge
wanted to see whether cerebral small vessel disease and other
cardiovascular risk factors damage the glymphatic system – and whether
this in turn increases the risk of dementia.
Until recently, it has only been possible to study glymphatic
function in mice, but recent advances in MRI scanning have made it
possible to study it indirectly in humans. Even so, it was only possible
to do this practically in relatively small numbers, but Yutong Chen,
while a medical student at the University of Cambridge, developed
machine learning algorithms capable of assessing glymphatic functions
from MRI scans at scale.
The team applied the algorithm to MRI scans taken from around 40,000
adults in UK Biobank. They found three biomarkers – biological
signatures – associated with impaired glymphatic function assessed at
baseline, predicted the risk of dementia occurring over the subsequent
decade. One of these was DTI-ALPS, a measure of the diffusion of water
molecules along the perivascular spaces. Another was the size of the
choroid plexus, where the CSF is produced. The third measure reflected
the flow velocity of CSF into the brain.
Although we have to be cautious about indirect markers, our work
provides good evidence in a very large cohort that disruption of the
glymphatic system plays a role in dementia. This is exciting because it
allows to ask: how can we improve this?"
Yutong Chen, Department of Clinical Neurosciences at Cambridge
Further analysis showed that several cardiovascular risk factors
impaired glymphatic function – and hence increased dementia risk, and
that this was partly via causing cerebral small vessel disease, which is
visible in the MRI scans.
First author Hui Hong, now a radiologist at the Second Affiliated
Hospital of Zhejiang University, Hangzhou, China, said: "We already have
evidence that small vessel disease in the brain accelerates diseases
like Alzheimer's, and now we have a likely explanation why. Disruption
to the glymphatic system is likely to impair our ability to clear the
brain of the amyloid and tau that causes Alzheimer's disease."
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The
research suggests possible approaches for reducing dementia risk. One
is to look at strategies for improving glymphatic function. Sleep plays
an important role in glymphatic function, and so disrupted sleep
patterns are likely to impair its ability to clear toxins.
Alternatively, there may be existing medicines that could be repurposed,
or new ones that could be developed, to improve glymphatic function.
Another possible approach is to treat vascular risk factors such as
high blood pressure. This is supported by recent studies: the SPRINT
MIND trial, for example, showed that intensive blood pressure control
(maintaining a systolic blood pressure of less than 120 mm Hg) led to a
20% reduction in cognitive decline or dementia compared to participants
in the standard treatment group.
Professor Markus, who leads the Stroke Research Group at the
University of Cambridge and is a Fellow of Clare Hall, Cambridge, said:
"We already know the importance of cardiovascular risk factors when it
comes to dementia, and our findings further emphasise this link.
"At least a quarter of all dementia risk is accounted for by common
risk factors like blood pressure and smoking. If these impair glymphatic
function, then we can intervene. Treating high blood pressure or
encouraging people to stop smoking would be an achievable way to helping
the glymphatic system work better."
Professor Bryan Williams, Chief Scientific and Medical Officer at the British Heart Foundation, said: "This
study offers us a fascinating glimpse into how problems with the
brain's waste clearance system could be quietly increasing the chances
of developing dementia later in life. By improving our understanding of
the glymphatic system, this study opens exciting new avenues for
research to treat and prevent dementia. It also emphasises the
importance of managing known cardiovascular risk factors, such as high
blood pressure, for reducing dementia risk."
The research was funded by the British Heart Foundation, with
additional support from the National Institute for Health and Care
Research Cambridge Biomedical Research Centre.
Source:
Journal reference:
Hong, H., et al. (2025) MRI markers of cerebrospinal fluid dynamics predict dementia and mediate the impact of cardiovascular risk. Alzheimer's & Dementia: The Journal of the Alzheimer's Association. doi.org/10.1002/alz.70699
