3 Sept 2012 - New Scientist - Food for thought: Eat your way to dementia - sugar and carbs cause 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."