Alzheimer’s: the missing link

C&I Issue 4, 2014

Characterised by steady cognitive decline, loss of memory and increasing confusion, the cause of Alzheimer’s disease has long eluded scientists. What is known is that a protein found widely throughout the body, amyloid precursor protein (APP), is broken down and turned into a shorter fragment known as beta-amyloid. Clumps of this protein fragment build up in the brain, forming sticky plaques and causing tangles to develop inside neurons, disrupting the vital transport of nutrients within cells. Although it is not known why, beta-amyloid is deeply toxic to the brain, causing the death of neurons and triggering inflammatory responses as the brain attempts to repair itself.

Type 2 diabetes, on the other hand, is a fairly well understood condition, which occurs when high levels of glucose accumulate in the blood. This happens because the body stops producing enough of the hormone insulin, responsible for moving glucose from the blood into cells so it can be used for energy. Cells in the liver, fat and muscles also stop responding to insulin, becoming insensitive to it.

On the face of it, the two conditions seem unrelated; however, a dramatic link between them was discovered in 1999 in the landmark Rotterdam study.1  This study tracked 6370 elderly men and women in the Netherlands over an average of two years and found that a significant proportion of the people who went on to develop Alzheimer’s disease  had diabetes. In fact the researchers concluded that having diabetes almost doubled the subjects’ risk of dementia.

Over the years, a number of studies have shown that diabetes is associated with cognitive problems such as memory loss and confusion. Some researchers believe that it is the disruption of glucose levels in the brain that is responsible.

‘The metabolism of glucose in the brain is particularly important in Alzheimer’s disease, and especially as we age,’ explains Frank Gunn Moore, professor of molecular neurobiology at St Andrews University in Scotland.

‘When we are babies, our brain uses glucose all the time as its main energy supply; however, as we age then our brains start to use other energy sources and particularly use a structure within nerve cells called “mitochondria” (the power cells of the neuron) to do this. The energy requirement of the adult brain is carefully balanced, but in diabetes this balance is lost and so this places an additional metabolic stress on the brain, which can result in an increased risk of developing Alzheimer’s disease,’ he adds.

However, other researchers believe that diabetes may contribute to Alzheimer’s more directly, with insulin playing a key role. A study in 2005 led by Suzanne de la Monte at Brown University in Connecticut, US,2  showed that it is not just liver, muscle and fat cells that become insensitive to insulin when a person becomes diabetic, so too do cells in a region of the brain known as the hippocampus, which is involved in learning and memory. This suggests that diabetes has an effect on the brain as well as the body.

Ewan McNay, professor of behavioural science at the University of Albany, New York, US, recently showed that rats fed on a diet high in fat and sugar in order to give them Type 2 diabetes had severe memory impairments, compared with those fed on a healthy diet. The rats were trained to associate a dark cage with an electric shock. Whenever the rats were returned to this dark cage, they froze, anticipating the pain that was about to come. However the rats that were diabetic froze in fear for a much shorter amount of time, showing that their memory was less good than the rats fed on the healthy diet.

His findings, presented at the annual Society for Neuroscience meeting in San Diego, US, in November 2013, together with the previous work on the topic suggest that the memory problems that often accompany Type 2 diabetes may, in fact, be early-stage Alzheimer’s rather than mere cognitive decline.

‘Our data suggest that the link between Type 2 diabetes and eventual development of Alzheimer’s disease may have consequences much earlier than was previously realised,’ says McNay. ‘We think that the cognitive impairment associated with Type 2 diabetes may in fact be early stage Alzheimer’s caused by abnormal amyloid accumulation,’ he adds.

But how exactly could diabetes cause Alzheimer’s? Until now scientists believed that the cognitive decline in people with Type 2 diabetes is because, as neurons in the hippocampus stop responding to insulin, they become less able to take in glucose and so stop producing the energy that is needed for them to function properly. However, research shows that  feeding animals a diet designed to give them Type 2 diabetes leaves their brains with insoluble plaques of beta-amyloid, associated with Alzheimer’s.

Spurred on by these findings, a trial has begun to see whether the diabetes drug liraglutide (Victoza) can slow the progression of Alzheimer’s disease. A recent study on the effect of the drug on mice, led by Christian Hölscher at Lancaster University, UK, showed that it might be able to reverse some of the damage caused by in the later stages of Alzheimer’s disease.3

Researchers gave the drug to mice with late-stage Alzheimer’s and found that they performed significantly better on an object recognition test, and that their brains showed a 30% reduction in the build-up of toxic beta amyloid plaques. A clinical trial of the drug has now begun on humans, led by Paul Edison of Imperial College London.  It is hoped that the drug will reduce brain inflammation, improving the growth of brain cells and the connections between them. As liraglutide is already licensed for diabetes, it should potentially be much cheaper and faster to develop as a new Alzheimer’s treatment. If the trial is successful, liraglutide could become a new treatment for Alzheimer’s disease within the next 5-10 years, helping many of the estimated 750,000 sufferers in the UK, as well as many more around the world and in the future.

Jessica Smith, research communications officer at the UK Alzheimer’s Society, says: ‘Alzheimer’s Society is currently part funding a study to test a Type 2 diabetes treatment, liraglutide, in people with dementia – however, the mechanisms by which this might work are still unclear. While liraglutide has a role for people with Type 2 diabetes in increasing the response to insulin, these types of drug may also have a neuroprotective effect unrelated to their use in diabetes.’

Meanwhile, diabetes is one of the few concrete risk factors for dementia, but how the two are connected has long remained a mystery. The research by McNay offers just one explanation. Another recent study,4 for example, has also found that chemicals called glycotoxins, present at high concentrations in fried and grilled meats,  may raise the risk of both diabetes and dementia. Helen Vlassara, who led the study at the Icahn School of Medicine at Mount Sinai in New York, US, found that mice raised on a western style diet that had high levels of a type of glycotoxin called advanced glycation end products (AGEs), had a high build-up of amyloid in their brains.

A small group of people over 60 with higher levels of glycotoxins in their circulation also had memory and other cognitive problems, and signs of insulin resistance, which precedes diabetes.

But while there is ‘a wealth of research linking the development of Type 2 diabetes with an increased risk of Alzheimer’s disease,’  the reasons underlying this have yet to be established, Smith says. ‘There remains insufficient research to draw any firm conclusions and we know that some of the factors relating to Type 2 diabetes – which include high blood pressure and obesity – increase the risk of Alzheimer’s disease independently of diabetes. Finding out more about the role insulin plays within the brain, and also the ways in which brain cells are sensitive to alterations in energy availability, is important in understanding the underlying changes that may occur during dementia.’

Jasmin Fox-Skelly is a freelance science writer based in Cardiff, UK


1 A. Ott et al, Neurology, 1999, 53, 1937.
2 E. Steen et al, J Alzheimers Dis., 2005, 7(1), 63.
3 P.L. McClean and C. Holscher, Neuropharmacology, 2013, 76, 57.
4 W Cal et al, PNAS, 2014: doi:10.1073/pnas. 1316013111

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