Editorial: 鈥�If diabetes causes Alzheimer鈥檚, we can beat it鈥�
HAVING type 2 diabetes may mean you are already on the path to Alzheimer鈥檚. This startling claim comes from a study linking the two diseases more intimately than ever before. There is some good news: the same research also offers a way to reverse memory problems associated with diabetes 鈥� albeit in rats 鈥� which may hint at a new treatment for Alzheimer鈥檚.
鈥淧erhaps you should use Alzheimer鈥檚 drugs at the diabetes stage to prevent cognitive impairment in the first place,鈥� says from the University at Albany in New York.
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Alzheimer鈥檚 cost the US $130 billion in 2011 alone. One of the biggest risk factors is having type 2 diabetes. This kind of diabetes occurs when liver, muscle and fat cells stop responding efficiently to insulin, the hormone that tells them to absorb glucose from the blood. The illness is usually triggered by eating too many sugary and high-fat foods that cause insulin to spike, desensitising cells to its presence. As well as causing obesity, insulin resistance can also lead to cognitive problems such as memory loss and confusion.
In 2005, a study by group at Brown University in Providence, Rhode Island, identified a reason why people with type 2 diabetes had a higher risk of developing Alzheimer鈥檚. In this kind of dementia, the hippocampus, a part of the brain involved in learning and memory, seemed to be insensitive to insulin. Not only could your liver, muscle and fat cells be 鈥渄iabetic鈥� but so it seemed, .
Feeding animals a diet designed to give them type 2 diabetes leaves their brains riddled with insoluble plaques of a protein called beta-amyloid 鈥� one of the calling cards of Alzheimer鈥檚. We also know that insulin plays a . Taken together, the findings suggest that Alzheimer鈥檚 might be caused by a type of brain diabetes.
If that is the case, the memory problems that often accompany type 2 diabetes may in fact be early-stage Alzheimer鈥檚 rather than mere cognitive decline.
Although there is no definitive consensus on the exact causes of Alzheimer鈥檚, we do know that brains get clogged with beta-amyloid plaques. One idea gaining ground is that it is not the plaques themselves that cause the symptoms, but their precursors 鈥� small, soluble clumps of beta-amyloid called oligomers. The insoluble plaques could actually be the brain鈥檚 way of trying to isolate the toxic oligomers.
To investigate whether beta-amyloid might also be a cause of cognitive decline in type 2 diabetes, McNay, Danielle Osborne and their colleagues fed 20 rats a high-fat diet to give them type 2 diabetes. These rats, and another 20 on a healthy diet, were then trained to associate a dark cage with an electric shock. Whenever the rats were returned to this dark cage, they froze in fear 鈥� measuring how long they stayed still is a standard way of inferring how good their memory is.
Memory boost
As expected, the diabetic rats had weaker memories than the healthy ones 鈥� they froze in the dark for less than half the time of their healthy counterparts. To figure out whether this was due to the beta-amyloid plaques or the soluble precursors, at the Rensselaer Polytechnic Institute in Troy, New York, engineered fragments of antibodies that disrupt the action of one or the other.
When the plaque-disrupting antibodies were injected into diabetic rats, no change was seen. However, after receiving antibodies specific for oligomers, they froze for just as long as the healthy rats. 鈥淭he cognitive deficit brought on by their diabetes is entirely reversed,鈥� says McNay.
Until now, the standard explanation for the cognitive decline associated with type 2 diabetes is that it is a result of insulin signalling gone awry. One effect is to reduce the hippocampus鈥檚 ability to transport energy, or glucose, to neurons during a cognitive task. The fact that amyloid builds up in the brains of diabetic animals 鈥� and also in people, was seen as an unhappy consequence of insulin imbalance.
These experiments suggest oligomers are actually to blame. Previous work from other groups has shown that the same enzymes break down both insulin and beta-amyloid oligomers 鈥� and that the in the hippocampus. So when there is too much insulin around 鈥� as there is in someone with type 2 diabetes 鈥� those enzymes are working flat out to break it down. This preferential treatment of insulin leaves the oligomers to form clumps, which then keep insulin from its receptors, causing a vicious spiral of impaired brain insulin signalling coupled with cognitive decline.
鈥淲e think that our treatment soaked up the amyloid oligomers, so that they could no longer block insulin from binding to its receptors,鈥� says McNay, who presented the preliminary data at the in San Diego earlier this month. 鈥淓veryone thinks of amyloid build-up as a consequence of the events that cause cognitive impairment in diabetes, but we鈥檙e saying it鈥檚 actually a cause.鈥� It means, he says, that the cognitive decline seen in type 2 diabetes may be thought of as early-stage Alzheimer鈥檚.
鈥淚t means that the cognitive decline seen in type 2 diabetes may be early stage Alzheimer鈥檚鈥�
It鈥檚 a bold claim, and if correct, one with big implications. Given that the number of people with type 2 diabetes is expected to jump from 382 million now to 592 million by 2035, we might expect to see a similar trajectory for associated Alzheimer鈥檚 (New 杏吧原创, 1 September 2012). If beta-amyloid build-up can be stopped in people with type 2 diabetes and their cognitive impairment reversed 鈥� perhaps many of them will never progress to Alzheimer鈥檚.
For the last few years, organisations like the UK鈥檚 Alzheimer鈥檚 Society have been backing clinical trials to look for . 鈥淲e鈥檙e saying that this may be not the only way to think about it,鈥� says McNay.
The next step is to repeat the work, and if the results are corroborated, start looking for a drug that would do the same thing as the group鈥檚 modified antibodies, without having to inject the drug directly into the hippocampus. It will also be necessary to work out just how much amyloid the brain can safely do without, since low levels are important for memory formation.
鈥淭he work opens the door to inoculating the most at risk group, people with type 2 diabetes,鈥� says of the University of Texas at Dallas. There have been plenty of failed attempts to use antibodies to relieve Alzheimer鈥檚 in the past. 鈥淏ut these were all in people with advanced stages of the disease. Vaccinating people much earlier could give better results.鈥�
Some researchers are still wary of focusing on beta-amyloid when 20 years of working on a treatment for that particular aspect of the disease has come to nothing. 鈥淚 think it鈥檚 brilliant work 鈥� he鈥檚 using new techniques that seem to be working, but it鈥檚 still very beta-centric,鈥� says at the University of Kentucky in Lexington. He cautiously agrees that McNay鈥檚 data do seem to suggest a causative link between beta-amyloid and impaired insulin signalling but says the group needs to factor in the effect of ageing 鈥� both diabetes and Alzheimer鈥檚 become more likely as we grow older.
Jessica Smith, spokeswoman for the UK Alzheimer鈥檚 Society in London welcomes the work. 鈥淲e need to tease out the difference between those with type 2 diabetes who develop Alzheimer鈥檚 and those who don鈥檛. If people were developing the signs earlier than we thought, then perhaps we can intervene earlier, rather than waiting until they have full clinical Alzheimer鈥檚.鈥�
Of course, there is another solution to staving off type 2 diabetes and any consequential Alzheimer鈥檚 that requires no drugs at all. 鈥淕o to the gym and eat fewer twinkies,鈥� says McNay.
This article appeared in print under the headline 鈥淓ating your way to dementia鈥�
