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Alzheimer's story 'overdone'

Tuesday 28 October 2008

The Daily Mail reports that “a popular epilepsy drug can reverse the early stages of Alzheimer’s disease”. It goes on to report that valproic acid (VPA) reduced the formation of “patches of sticky protein, or plaques, that clog the brain in Alzheimer’s” and improved memory in tests on mice. The newspaper reports that these results were so encouraging that a pilot trial in humans with Alzheimer’s has begun. Professor Clive Ballard, who is director of research at the Alzheimer’s Society, is quoted as saying: “Although this is encouraging evidence, valproic acid …had a number of side effects. We wouldn’t currently recommend it as a clinical treatment for Alzheimer’s. We look forward to the results of ongoing human trials."

This preliminary research in mice does indicate that VPA can reduce plaque formation in mouse brains, but did not show that it could “reverse” damage that has already been caused; this is also supported by the fact that effects on memory only occurred if VPA was given early enough. Until the results are obtained from the human trials, it remains unclear whether similar effects can be seen in humans with Alzheimer’s.

Where did the story come from?

Dr Hong Qing and colleagues from the University of British Columbia and other research centres in Canada, China, Switzerland and the US carried out this research. The study was funded by the Canadian Institutes of Health Research, Jack Brown and Family Alzheimer’s Research Foundation, and the Michael Smith Foundation for Health Research. The study was published in the peer-reviewed Journal of Experimental Medicine.

What kind of scientific study was this?

This was a laboratory study in mice. It looked at the effects of the drug valproic acid (VPA) on the formation of amyloid beta plaques in the brains of mice genetically engineered to develop an Alzheimer’s-like condition (APP23 and APP23/PS45 mice). It also looked at the drug’s effects on brain cells from these mice, and on their ‘memory’ behaviour.

People with Alzheimer’s disease develop two types of abnormal clumps of proteins within their nerve cells, called plaques and tangles. The main protein found in the plaques is amyloid beta, which is formed when a larger protein called beta amyloid precursor protein (APP) is broken down by enzymes called secretases. It is thought that the plaques and tangles contribute to the death of the nerve cells. Researchers think that by blocking their formation it might be possible to slow or stop Alzheimer’s disease. VPA is a drug that is used to treat epilepsy and bipolar disorder (sometimes called manic depression).

The researchers gave daily injections of VPA to a group of APP23 mice from seven or nine months of age. A group of age-matched mice were injected with a control solution not containing VPA. After four weeks of treatment, a memory test (the Morris water maze test) was given to both groups of mice, and their performance was compared. The memory test involves placing the mouse in a swimming tank with an escape platform. In the first set of tests, the platform is visible to the mice, but in the second set it is hidden a few millimetres under the surface of the water. The test assesses how well the mice remember where the platform is, by measuring how much they have to swim around and how long it takes them to find the platform. The experiment is repeated at hourly or 24 hourly intervals. In the final test, the platform is removed, and the researchers measure how long the mice spend looking in the area of the tank where the platform was previously located.

The researchers also looked at the mice’s brains to see how many amyloid beta plaques had built up in both groups (VPA treated and control) either immediately after treatment, or one or two months later. The researchers carried out similar experiments in another type of genetically engineered mouse called APP23/PS45 mice, which normally develop plaques earlier than the APP23 mice, by one month of age. These mice were given VPA from six weeks of age. The researchers then looked at how VPA might have an effect on amyloid beta plaques, by measuring the amounts of APP and amyloid beta in the VPA treated and untreated mice’s brains.

What were the results of the study?

The researchers found that after four weeks of VPA treatment, the number of amyloid beta plaques in the brains of seven-month-old APP23 mice reduced about four-fold compared with control. These effects still seemed to be present up to two months after treatment. The treatment also reduced plaque formation in nine-month-old APP23 mice by about two-fold, and by about five-fold in six-week-old APP23/PS45 mice.

When the mice’s ability to reach a visible escape platform in a swimming tank was tested, no difference was found between VPA-treated and untreated seven-month-old APP23 mice. This showed that the mice had the same visual and swimming abilities. However, when the platform was hidden under the water’s surface so the mice had to remember where it was, the VPA treated mice could remember where the platform was better than the untreated mice by the third and fourth day of testing. When the researchers repeated these tests on the nine-month-old APP23 mice, they found no difference in the performance of VPA treated and untreated groups. In APP23/PS45 mice, VPA treatment did not have an effect on how quickly they found the hidden platform or on how much they swam around before finding it. However, VPA treated mice did spend more time looking in the area of the pool where the platform had been, in the test where the platform was removed.

When the researchers looked at the mice’s brains, the researchers found that VPA treated mice had higher levels of APP in their brains, and lower levels of amyloid beta than control mice. A similar effect was seen when VPA was applied to nerve cells from APP23/PS45 mice in the laboratory.

What interpretations did the researchers draw from these results?

The researchers concluded that VPA reduced plaque formation in the brain and improved memory deficits in a genetically modified mouse model of Alzheimer’s disease. The effects on memory were only seen if VPA was given at an early stage. They say that this “suggests that VPA may be beneficial in the prevention and treatment of [Alzheimer’s disease]”.

What does the NHS Knowledge Service make of this study?

This study indicates that VPA has some effect on the formation of amyloid beta plaques in genetically modified mice with an Alzheimer’s-like condition. This may result in memory improvements if treatment is given early enough. However, it is too early to know whether VPA would offer similar benefits in humans. Substantial benefits in memory were only seen in one strain of mice (the APP23 mice) and only in those treated at an early stage of their disease. Additionally, the experiments were relatively short term.

It is unclear how well this test of memory represents the complex cognitive defects seen in humans with Alzheimer’s, which in addition to memory impairment, includes other problems with language, recognition and daily functioning. As VPA is already a drug approved for use in humans, it would have been easier for researchers to gain approval for testing the drug in treating Alzheimer’s in humans, and newspapers report that such a trial has already begun. VPA has previously been tested in people with Alzheimer’s disease for treating agitation, but was not found to have a significant effect on this outcome. It also carries a risk of side effects such as sedation at higher doses. These risks would have to be weighed up against any potential benefits found in future trials.

Analysis by Bazian
Edited by NHS Website

Links to the science

Further readingLonergan ET, Luxenberg J.

Valproate preparations for agitation in dementia.

Cochrane Database Syst Rev 2004, Issue 2

Qing H, He G, Ly PTT et al.

Valproic acid inhibits Aβ production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models.

J Exp Med 2008; Oct 27