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Editorial: 鈥�Brain diabetes: the ultimate food scare鈥�

SUZANNE DE LA MONTE鈥檚 rats were disoriented and confused. Navigating their way around a circular water maze 鈥� a common memory test for rodents 鈥� they quickly forgot where they were, and couldn鈥檛 figure out how to locate the hidden, submerged safety platform. Instead, they splashed around aimlessly. 鈥淭hey were demented. They couldn鈥檛 learn or remember,鈥� says de la Monte, in Providence, Rhode Island.

A closer look at her rats鈥� 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鈥檚 disease, and yet they arose in surprising circumstances. De la Monte had interfered with the way the rats鈥� 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鈥� 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鈥檚 have led some researchers to wonder whether Alzheimer鈥檚 may sometimes be another version of diabetes 鈥� one that hits the brain. Some have even renamed it 鈥渢ype 3 diabetes鈥�.

115m people globally will get Alzheimer鈥檚 by 2050

If they are right 鈥� and a growing body of evidence suggests they might be 鈥� the implications are deeply troubling. Since calorific foods are known to impair our body鈥檚 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. 鈥淭he epidemic of type 2 diabetes, if it continues on its current trajectory, is likely to be followed by an epidemic of dementia,鈥� says of the University at Albany in New York. 鈥淭hat鈥檚 going to be a huge challenge to the medical and care systems.鈥�

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 鈥� or at least decelerate 鈥� some of the cognitive decline in people who already have Alzheimer鈥檚, 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鈥檚

A new understanding of Alzheimer鈥檚 can鈥檛 come soon enough; it plagues an estimated 5.4 million adults in the US, whose care cost $130 billion in 2011 alone. Worldwide, , a figure that will rise as the population continues to grow. 鈥淲e are desperate for an effective therapy,鈥� says , a neurologist specialising in Alzheimer鈥檚 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. 鈥淓ventually, 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,鈥� 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鈥檚 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鈥檚 more, it encourages plasticity 鈥� 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 鈥渕akes evolutionary sense鈥�, 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 鈥渞emember this, it鈥檚 important鈥�, 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鈥檛 mop up glucose and fat in the blood. As a result, the pancreas desperately works overtime to make more insulin to control the glucose 鈥� and levels of the two molecules skyrocket. 鈥淚t鈥檚 like you are knocking on the door and the person inside is ignoring your call. So you knock louder and louder,鈥� says de la Monte. The pancreas can鈥檛 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 鈥� 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鈥檚. 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鈥檛 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. 鈥淚 believe it starts with insulin resistance,鈥� says de la Monte. 鈥淚f you can avoid brain diabetes you鈥檒l be fine. But once it gets going you are going to need to attack on multiple fronts.鈥�

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鈥檚, including the build-up of the deadly beta amyloid plaques.

De la Monte鈥檚 finding is now just one of many discoveries to confirm that a disrupted insulin system can lead to the symptoms of Alzheimer鈥檚. at Northwestern University in Evanston, Illinois, for instance, has found that triggering diabetes created Alzheimer鈥檚-like brain changes in rabbits, including a sharp rise in the number of beta amyloid proteins (). 鈥淚t鈥檚 the first time that any culprit has been singled out as an instigator of sporadic Alzheimer鈥檚 disease pathology, one of the big mysteries in the field,鈥� 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 鈥渕uch like an Alzheimer鈥檚 patient鈥�, 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鈥檚 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鈥檚 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鈥檚 barely reacted at all (). 鈥淭he insulin signalling is paralysed,鈥� says Arnold.

$130bn: the cost of Alzheimer鈥檚 care in the US in 2011

It鈥檚 not yet fully understood exactly why disrupted insulin signalling would lead to the other kinds of brain damage associated with Alzheimer鈥檚, such as the build up of plaques, though the emerging research suggests many, possibly interlinked, mechanisms (see 鈥淎 toxic cycle鈥�). 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 ().

40%: decrease in the risk of Alzheimer鈥檚 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 (). 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. 鈥淚t triggers a vicious cycle,鈥� 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. 鈥淏ut 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,鈥� he says.

It is still early days for this work 鈥� and the researchers are keen to point out that they haven鈥檛 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鈥檚 searching for other culprits. Suzanne Craft, who has been a pioneer in insulin and Alzheimer鈥檚 research, agrees that it is probably one of many paths to the disease. After all, most people with Alzheimer鈥檚 don鈥檛 have full-blown type 2 diabetes 鈥� though many do have some problems with the insulin signalling in their bodies, even if they don鈥檛 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 鈥減rediabetic鈥�, showing some of the early signs of insulin resistance. If Alzheimer鈥檚 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鈥檛 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 鈥� none of whom had diabetes 鈥� 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. 鈥淎n unhealthy diet disrupts normal insulin function in the brain, increases inflammation and oxidative stress, and impairs amyloid regulation,鈥� says Craft. When these three converge they can lead to Alzheimer鈥檚, 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鈥檚. 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 ().

98m people in the US show some signs of insulin resistance, putting them at greater risk of Alzheimer鈥檚

Given insulin鈥檚 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 鈥� both of which are problems for people with Alzheimer鈥檚. Klein, meanwhile, thinks that Craft鈥檚 approach may work because insulin helps prevent the beta amyloid toxins from docking with brain cells. 鈥淚t is a struggle between insulin and the toxins for synaptic survival,鈥� 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鈥檚 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. 鈥淲e want to see if these medicines work to decrease levels of these abnormal proteins in Alzheimer鈥檚 disease and ultimately improve the patients鈥� cognitive abilities, or at least prevent them from getting worse,鈥� he says. 鈥淲e鈥檒l also see whether the drugs restore other insulin functions like promoting synapse formation and regrowing neural connections.鈥� 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鈥檚. Conversely, diets rich in certain kinds of fatty acids might help the brain to maintain good insulin signalling (see 鈥�Food for thought鈥�). Exercise, too, can encourage the body to conquer insulin resistance 鈥� which may explain why regular physical activity reduces your risk of Alzheimer鈥檚 by 40 per cent (Annals of Internal Medicine, vol 144, p 73).

鈥淓ven if you are 400 pounds and you haven鈥檛 seen the back of the couch for six months, it鈥檚 not too late. It鈥檚 likely that any exercise will help, even in patients who鈥檝e been diabetic for a long time. Get some of the insulin sensitivity back and stop accumulating so much amyloid,鈥� says McNay. 鈥淧otentially, even some of the amyloid that鈥檚 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.鈥�