Health
03 September 2012
Sugar junkies take note: a calorific diet isn't just bad for your body, it may also trigger Alzheimer's disease
SUZANNE DE LA MONTE's rats were
disoriented and confused. Navigating their way around a circular water
maze - a common memory test for rodents - they quickly forgot where they
were, and couldn't figure out how to locate the hidden, submerged
safety platform. Instead, they splashed around aimlessly. "They were
demented. They couldn't learn or remember," says de la Monte,
a neuropathologist at Brown University in Providence, Rhode Island.
A closer look at her rats' brains
uncovered devastating damage. Areas associated with memory were studded
with bright pink plaques, like rocks in a climbing wall, while many
neurons, full to bursting point with a toxic protein, were collapsing
and crumbling. As they disintegrated, they lost their shape and their
connections with other neurons, teetering on the brink of death.
Such changes are the hallmarks of
Alzheimer's disease, and yet they arose in surprising circumstances. De
la Monte had interfered with the way the rats' brains respond to
insulin. The hormone is most famous for controlling blood sugar levels,
but it also plays a key role in brain signalling. When de la Monte
disrupted its path to the rats' neurons, the result was dementia.
Poor sensitivity to insulin is
typically associated with type 2 diabetes, in which liver, fat and
muscle cells fail to respond to the hormone. But results such as de la
Monte's have led some researchers to wonder whether Alzheimer's may
sometimes be another version of diabetes - one that hits the brain. Some
have even renamed it "type 3 diabetes".
115m people globally will get Alzheimer's by 2050
If they are right - and a growing body
of evidence suggests they might be - the implications are deeply
troubling. Since calorific foods are known to impair our body's response
to insulin, we may be unwittingly poisoning our brains every time we
chow down on burgers and fries. People with type 2 diabetes, who have
already developed insulin resistance, may be particularly at risk. "The
epidemic of type 2 diabetes, if it continues on its current trajectory,
is likely to be followed by an epidemic of dementia," says
Ewan McNay of the University at Albany in New York. "That's going to be a huge challenge to the medical and care systems."
All of which highlights the importance
of eating healthier foods and taking exercise to reduce your risk of
dementia. It may even be possible to reverse - or at least decelerate -
some of the cognitive decline in people who already have Alzheimer's, by
targeting the underlying insulin resistance. If so, that would suggest
new treatments for the disease, which has so far evaded any attempt to
treat it.
35.7% of people in the US are obese, putting them at greater risk of Alzheimer's
A new understanding of Alzheimer's
can't come soon enough; it plagues an estimated 5.4 million adults in
the US, whose care cost $130 billion in 2011 alone. Worldwide,
36 million people have the disease, a figure that will rise as the population continues to grow. "We are desperate for an effective therapy," says
John Morris, a neurologist specialising in Alzheimer's disease at the Washington University School of Medicine in St Louis.
For a long time, the finger of blame has pointed squarely at
the beta amyloid plaques
that amass in the brains of people with the disease. Alois Alzheimer,
the German psychiatrist and neuropathologist for whom the disease is
named, first described these strange protein deposits over a century
ago, when he noticed apparently normal brain cells filled with strange
fibrils. In the areas where the disease had progressed, the fibrils had
merged and moved to the surface inside the cell, where they folded
together in thick bundles. "Eventually, the nucleus and the cell
disintegrate, and only a tangled bundle of fibrils indicates the place
which had formerly been occupied by a ganglion cell," he wrote.
The origin of these plaques is only
partially understood; we know that beta amyloid is a fragment of a
larger protein that helps form cell membranes in the brain and other
parts of the body. It is also thought to carry out important functions
of its own, such as fighting microbes, transporting cholesterol and
regulating the activity of certain genes. What prompts the protein to
clump into the deadly plaques is something of a mystery, but if the new
research is right, a diabetes-like illness might be a trigger.
This new focus follows a growing
recognition of insulin's role in the brain. Until recently, the hormone
was typecast as a regulator of blood sugar, giving the cue for muscles,
liver and fat cells to extract sugar from the blood and either use it
for energy or store it as fat. We now know that it is a master
multitasker: it helps neurons, particularly in the hippocampus and
frontal lobe, take up glucose for energy, and it also regulates
neurotransmitters, like acetylcholine, which are crucial for memory and
learning. What's more, it encourages plasticity - the process through
which neurons change shape, make new connections and strengthen others.
And it is important for the function and growth of blood vessels, which
supply the brain with oxygen and glucose.
As a result, reducing the level of
insulin in the brain can immediately impair cognition. Spatial memory,
in particular, seems to suffer when you block insulin uptake in the
hippocampus; the effect is almost the same as that of morphine, says
McNay. Conversely, a boost of insulin seems to improve its functioning.
McNay points out that this role in the
brain "makes evolutionary sense", since it would help us to remember
the location of a food source. As our ancestors gorged on berries in the
savannah, for instance, the spike in glucose and the subsequent rush of
insulin would signal "remember this, it's important", causing the brain
to crystallise the memory.
But as we know from type 2 diabetes,
processes that evolved to help us meet the challenges of prehistory can
easily backfire in the modern world. When people frequently gorge on
fatty, sugary food their insulin spikes repeatedly until it sticks at a
higher level. Muscle, liver and fat cells then stop responding to the
hormone, meaning they don't mop up glucose and fat in the blood. As a
result, the pancreas desperately works overtime to make more insulin to
control the glucose - and levels of the two molecules skyrocket. "It's
like you are knocking on the door and the person inside is ignoring your
call. So you knock louder and louder," says de la Monte. The pancreas
can't keep up with the demand indefinitely, however, and as time passes
people with type 2 diabetes often end up with abnormally low levels of
insulin.
Weight gain seems to amplify the
problem - 80 per cent of people with type 2 diabetes are also overweight
or obese. Though the mechanism is still unclear, obesity seems to
trigger the release of inflammatory and metabolic stress molecules
inside liver and fat cells that disrupt insulin action, leading to high
blood glucose levels and, eventually, insulin resistance.
If McNay and de la Monte are correct, a
similar process may lead to Alzheimer's. They think that constantly
high levels of insulin, triggered by the fat and sugar content of the
western diet, might begin to overwhelm the brain, which can't constantly
be on high alert. Either alongside the other changes associated with
type 2 diabetes, or separately, the brain may then begin to turn down
its insulin signalling, impairing your ability to think and form
memories before leading to permanent neural damage. "I believe it starts
with insulin resistance," says de la Monte. "If you can avoid brain
diabetes you'll be fine. But once it gets going you are going to need to
attack on multiple fronts."
Her study on the demented rats was one
of the first experiments to make this link. At the time she was
interested in the impact of alcohol on the brain, which is known to
decrease its number of insulin receptors. To probe the consequences she
used a chemical to wipe out all the brain cells carrying the insulin
receptor; the result looked surprisingly similar to Alzheimer's,
including the build-up of the deadly beta amyloid plaques.
De la Monte's finding is now just one
of many discoveries to confirm that a disrupted insulin system can lead
to the symptoms of Alzheimer's.
William Klein
at Northwestern University in Evanston, Illinois, for instance, has
found that triggering diabetes created Alzheimer's-like brain changes in
rabbits, including a sharp rise in the number of beta amyloid proteins (
The Journal of Alzheimer's Disease, DOI: 10.3233/JAD-2012-120571).
"It's the first time that any culprit has been singled out as an
instigator of sporadic Alzheimer's disease pathology, one of the big
mysteries in the field," he says. McNay and Suzanne Craft at the
University of Washington in Seattle, meanwhile, fed rats a high fat diet
for 12 months, which destroyed their ability to regulate insulin and
led to diabetes. Once again, the change was accompanied by high beta
amyloid levels in the brain. They also had trouble navigating a maze and
looked "much like an Alzheimer's patient", says McNay.
Of course, animal studies can only
tell you so much about a human disease, but an almost Frankensteinian
demonstration confirms that the brains of people with Alzheimer's are
insulin-resistant. Using brains from cadavers, Steven Arnold at the
University of Pennsylvania bathed various tissue samples in insulin to
see how they would react. Tissue from people who had not had Alzheimer's
seemed to spring back to life, triggering a cascade of chemical
reactions suggestive of synaptic activity. In contrast, the neurons of
those who had had Alzheimer's barely reacted at all (
Journal of Clinical Investigations, vol 122, p 1316). "The insulin signalling is paralysed," says Arnold.
$130bn: the cost of Alzheimer's care in the US in 2011
It's not yet fully understood exactly
why disrupted insulin signalling would lead to the other kinds of brain
damage associated with Alzheimer's, such as the build up of plaques,
though the emerging research suggests many, possibly interlinked,
mechanisms (see "
A toxic cycle").
One line of evidence, for instance, has shown that insulin and beta
amyloid are both broken down by the same protein-chomping enzyme. Under
normal circumstances that enzyme can successfully deal with both, but if
too much insulin is washing around, the enzyme gets overwhelmed by the
hormone, and the beta amyloid gets neglected. Instead of being broken
down, it accumulates, perhaps building into the toxic plaques that kill
brain cells (
Proceedings of the National Academy of Sciences, vol 100, p 4162).
40%: decrease in the risk of Alzheimer's from regular exercise
Exacerbating the problem, beta amyloid
can then stop neurons from responding to insulin, leading to further
damage. By studying dishes of rat neurons, Klein has found that toxic
clusters of the protein attack and destroy regions of synapses that are
covered in insulin receptors; they also stop new receptors appearing,
making the neuron insulin-resistant (
FASEB Journal, vol 22, p 246).
The result would be an immediate impairment in cognition. Worse still,
this insulin resistance tells the cells to make even more beta amyloid,
which then goes on to harm more brain cells. "It triggers a vicious
cycle," says Klein.
Things only get worse if the pancreas
becomes exhausted by the high demand for insulin, lowering levels of the
hormone in the brain. Klein has found that a moderate level of insulin
is protective, offsetting beta amyloid damage by blocking its landing
sites on brain cells. "But when people age or have diabetes, the insulin
signalling in the brain becomes weaker, possibly opening a window for
amyloid beta toxin to start destroying the neurons," he says.
It is still early days for this work -
and the researchers are keen to point out that they haven't solved
every aspect of the puzzle. Klein, for example, thinks that lack of
insulin in the brain may be just one of many triggers for beta amyloid
toxins, so he's searching for other culprits. Suzanne Craft, who has
been a pioneer in insulin and Alzheimer's research, agrees that it is
probably one of many paths to the disease. After all, most people with
Alzheimer's don't have full-blown type 2 diabetes - though many do have
some problems with the insulin signalling in their bodies, even if they
don't match every criterium for the disease.
Even so, the research should ring
warning bells for the future. Thanks to our addiction to fast food, type
2 diabetes is constantly on the rise (
see graph).
In the US alone, 19 million people have now been diagnosed with the
condition, while a further 79 million are considered "prediabetic",
showing some of the early signs of insulin resistance. If Alzheimer's
and type 2 diabetes do share a similar mechanism, levels of dementia may
follow a similar trajectory as these people age.
Even if someone doesn't develop
diabetes, a bad diet might be enough to set the wheels in motion for
brain degeneration, according to an ongoing study led by Craft. For one
month a group of volunteers - none of whom had diabetes - ate foods that
were high in saturated fat and sugar while a control group ate a diet
low in sugar and saturated fat. In just four weeks, those gorging on the
high-sugar diet had higher levels of insulin and significantly higher
beta amyloid levels in their spinal fluid. The control group showed
decreases in both. "An unhealthy diet disrupts normal insulin function
in the brain, increases inflammation and oxidative stress, and impairs
amyloid regulation," says Craft. When these three converge they can lead
to Alzheimer's, she says. When you consider that obesity is a big risk
factor for both diabetes and dementia, all the signs suggest that our
addiction to junk foods could spell trouble for our mental health in the
future.
On the plus side, a new understanding
of the disease might lead to new treatments for those who already have
Alzheimer's. Craft, for instance, is investigating whether a boost of
insulin might improve symptoms. So far, she has tested out a device that
delivers insulin deep into the nose, where it then travels to the
brain. The study was short, lasting just four months and involving only
104 people, but the results were promising. In memory tests those who
received the treatment could recall more details of stories, had longer
attention spans, regained more interest in their hobbies and were better
able to care for themselves. The glucose metabolism in their brains
also improved (
Archives of Neurology, vol 69, p 29).
98m people in the US show some signs of insulin resistance, putting them at greater risk of Alzheimer's
Given insulin's many roles in the
brain, the nasal spray may work for a number of reasons. A blast of the
hormone might help struggling cells to return to normal activity.
Alternatively, Craft points out that it might decrease inflammation and
oxidative stress caused by reactive oxygen-containing compounds - both
of which are problems for people with Alzheimer's. Klein, meanwhile,
thinks that Craft's approach may work because insulin helps prevent the
beta amyloid toxins from docking with brain cells. "It is a struggle
between insulin and the toxins for synaptic survival," he says. He
suspects it might also curb the build-up of these toxins in the first
place.
A better understanding of this process
might come from Craft's next project; she has just been awarded $7.9
million by the US National Institutes of Health in Bethesda, Maryland,
to test the nasal insulin spray on 240 volunteers showing signs of
dementia. Teams across the US will monitor learning, memory, daily
function and any brain changes using PET scans.
There are several other possible lines
of attack: clinical trials are investigating the use of approved
diabetes drugs such as metformin, exenatide, liraglutide and
pioglitazone, which try to restore the balance of insulin and glucose in
the blood or improve the insulin sensitivity of an organ. Arnold, for
instance, plans to study the effect of metformin by measuring amyloid
levels in the spinal fluid and testing the blood flow in the brain
before and after treatment. "We want to see if these medicines work to
decrease levels of these abnormal proteins in Alzheimer's disease and
ultimately improve the patients' cognitive abilities, or at least
prevent them from getting worse," he says. "We'll also see whether the
drugs restore other insulin functions like promoting synapse formation
and regrowing neural connections." Other groups plan to use advanced
brain imaging to see if these diabetes medications can shrink the beta
amyloid plaques, which might reverse some of the brain damage.
For the time being, there are measures
that everyone can take to help stave off cognitive decline. Since
insulin resistance emerges from a bad diet, laying off fatty and sweet
foods might help to reduce the risk of developing Alzheimer's.
Conversely, diets rich in certain kinds of fatty acids might help the
brain to maintain good insulin signalling (see "
Food for thought").
Exercise, too, can encourage the body to conquer insulin resistance -
which may explain why regular physical activity reduces your risk of
Alzheimer's by 40 per cent (
Annals of Internal Medicine, vol 144, p 73).
"Even if you are 400 pounds and you
haven't seen the back of the couch for six months, it's not too late.
It's likely that any exercise will help, even in patients who've been
diabetic for a long time. Get some of the insulin sensitivity back and
stop accumulating so much amyloid," says McNay. "Potentially, even some
of the amyloid that's built up might get broken down. As for the rest of
us, extra trips to the gym are always a good idea, and this work shows
that they help your brain as well as your body."
Diabetes of brain and body
Type 1: Only about 5 per cent of people with
diabetes have type 1, also called juvenile diabetes, which is typically
diagnosed in children and young adults. It starts when an autoimmune
response destroys the insulin-producing cells in the pancreas, meaning
the body can no longer regulate levels of blood sugar. Insulin therapy
helps these individuals lead a healthy life.
Type 2: Most people with diabetes have type
2. Here, the pancreas either does not produce enough insulin or the
muscle, liver and fat cells ignore the insulin and fail to suck excess
sugar from the blood. This can lead to both high insulin levels and high
blood sugar - the hallmarks of type 2 - which can raise the risk of
heart disease, stroke, blindness, nerve damage and amputation. Being
overweight, particularly if you have excess abdominal fat, increases
your risk of developing type 2 diabetes.
Type 3: This controversial new category,
coined by Suzanne de la Monte, refers to Alzheimer's disease, which she
and a growing number of other researchers believe arises when brain
tissue becomes resistant to insulin. In that sense it is like type 2 but
primarily concerns the brain.
Food for thought
Brain food isn't just an expression. Recent studies
have revealed that consuming a lot of foods high in saturated fat and
sugar or anything with a high glycaemic index are bad for your brain
because they keep your insulin levels high.
A recent study from the University of California,
Los Angeles, showed that rats consuming water laced with high-fructose
corn syrup, a sweetener in soft drinks, condiments and many processed
foods, had learning and memory problems after just six weeks, and their
brain tissue became less responsive to insulin.
But certain dishes may offer some protection against
these effects. Rats consuming high-fructose corn syrup water alongside
omega-3-fatty acids from flaxseed oil seemed to escape the cognitive
problems the other group encountered (
Journal of Physiology, vol 590, p 2485). Omega-3 acids are also found in oily fish.
There is also some tentative evidence that certain
compounds called flavonoids, found in tea, red wine and dark chocolate,
can reduce the risk of dementia. All of which may explain why the
Mediterranean diet is associated with less cognitive decline, dementia
and Alzheimer's disease. This diet is known to be rich in fish and
vegetable oils, non-starchy vegetables, low glycaemic fruits, less added
sugar and a moderate helping of wine (
Current Alzheimer Research, vol 8, p 520).
Bijal Trivedi is a writer based in Washington DC
- From issue 2880 of New Scientist magazine, page 32-37.
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