74 Science & technology The Economist April 2nd 2022
TheglymphaticsystemanddementiaBrain drain
I
nmostbodily organswastematteris
cleared out by the lymphatic system. Un
necessary proteins, superfluous fluids and
so on are carried away by special vessels to
lymph nodes, where they are filtered out
and destroyed. The more active the organ,
the more of these vessels there are. The ex
ception is the brain, which has none. It was
thus thought until recently that brain cells
broke down nearby waste products in situ.
But a paper published in 2012 reported
that the brain has a plumbing system of its
own to flush out the junk. Researchers
working in the laboratory of Maiken Ne
dergaard, at University of Rochester, in
New York state, showed that cerebrospinal
fluid—the liquid which suspends the brain
and acts as a cushion between it and the
skull—was actively washing through the
organ by hitchhiking on the pulsing of ar
teries and veins that happens with every
heartbeat. The fluid was collecting trash
and carrying it out of the brain to lymph
nodes for disposal. Now, ten years later,
the discovery of this “glymphatic” system,
so called because of the involvement of
brain cells known as glia, has opened up
new opportunities for the treatment of
brain disorders. Brainwashing
From the first studies of the glymphatic
system, it was clear it might be involved in
preventing Alzheimer’s disease. Alzheim
er’s is caused by a buildup of two types of
proteins, amyloidbeta and tau. These ag
gregate to form plaques and tangles that
stop neurons working properly and even
tually lead to their death. When it is func
tioning normally, the glymphatic system
clears out amyloidbeta and tau. However,
in older people, or those with Alzheimer’s,
this process is slower—leaving more po
tentially harmful proteins behind.
Giving the brain a power wash, by im
proving the flow of glymphatic fluid, is a
potential avenue for treatment. Though
the field is in its infancy, most attempts to
do so have focused on an interesting quirk
of the system. This is that glymphatic fluid
moves through the brain only during sleep.
The plumbing is disabled during waking
hours, and is most active during the deep
est sleep stages, switched on by slowwave
brain activity.
That discovery has changed how re
searchers think about the role of sleep, and
also about the link between sleep and neurologicaldisorders.Formanydiseases, in
cluding Alzheimer’s, a lack of sleep earlier
in life increases the risk. Dr Nedergaard
thinks that inadequate glymphatic clear
ance is the reason. Even a single night of
sleep deprivation can increase the amount
of amyloidbeta in the brain.
Many drugs affect sleep, sometimes as a
sideeffect of their main purpose. A study
published in Brain earlier this year fol
lowed almost 70,000 Danes who were be
ing treated for high blood pressure, using
betablockers. Some, but not all, types of
betablockers are able to enter the brain by
passing through the bloodbrain barrier.
This is a system of tight junctions between
cells lining blood vessels in the brain,
which exists to stop the admission of mol
ecules that might upset the function of the
organ. Once there, these beta blockers af
fect normal patterns of sleep and wakeful
ness. That, in turn, promotes glymphatic
circulation. Those in the study who took
barriercrossing betablockers every day
were less likely to develop Alzheimer’s
than people taking betablockers which
could not enter the brain.
Another medicine, suvorexant, which
is used to treat insomnia, also shows pro
mise. In one recent study, mice with a mu
tation that causes earlyonset Alzheimer’s
in people, and similar symptoms in ro
dents, were given this drug. Mutated mice
receiving suvorexant experienced less
build up of amyloidbeta. Even more remarkably, the drug also reversed their cog
nitive decline. In a maze test, mutated
mice on suvorexant performed as well as
healthy, unmutated ones. A preliminary
human trial of this effect is now under way.
Sleeppromoting drugs can, however,
have bad sideeffects. Indeed, in many cas
es, including the Danish study, they in
crease the risk of death from other causes.
Other people are therefore trying to boost
glymphatic clearance by different means.
One project, examining mice genetical
ly engineered to be prone to Alzheimer’s,
found that increasing slowwaves during
sleep, thus boosting fluid flow through the
brain, reduced the amount of amyloid
build up. This work involved “optogenet
ics”, in which cells are genetically engi
neered to respond to light, which is obvi
ously a nonstarter for a treatment for peo
ple. But a similar effect can be induced
harmlessly in humans by noninvasive
electrical stimulation.Call the plumber
Some studies report that such stimulation
can improve memory formation in the el
derly. And it may also be relevant to the
young and fit. America’s Department of De
fence is paying for at least two projects
which have the goal of developing wear
able caps to improve glymphatic flow dur
ing sleep in this way. Lack of sleep is a big
problem in the armed forces. During com
bat, getting a solid eight hours can be hard,
and lack of sleep inevitably affects a sol
dier’s performance.
As well as emphasising the importance
of a good night's sleep, the discovery of the
glymphatic system has highlighted other
ways that a healthy life can promote a clean
and tidy brain. In mice, exercise improves
glymphatic flow, flushing out amyloidbe
ta. By contrast, high blood pressure, which
prevents the normal pulsing of arteries
and veins that drives the system, reduces
fluid movement. In this context it is no
surprise that hypertension during middle
age increases the risk of developing Alz
heimer's disease later on in life.
The glymphatic system’s discovery has
had effects outside Alzheimer’s research,
too. Traumatic head injury, Parkinson’s
disease and mood disorders are all linked
to glymphatic clearance. There is hope, as
well, that this newly found plumbing may
help with the delivery of brain drugs. Get
ting medicines past the bloodbrain barri
er is notoriously difficult. Injecting them
into the cerebrospinal fluid directly, then
allowing them to wash throughout the
brain during sleep, may be simpler.
Decades of Alzheimer’s research has
left behind a graveyard of failed drug trials.
The brain’s plumbing network is providing
new targets, and new ways to thinkabout
treatments for the disease. The glymphatic
system, then, is at last being tapped.nTweaking the brain’s plumbing may help delay Alzheimer’s disease