© Al Bello / GettyDoes a healthy body lead to a healthy brain?
"What we've found is absolutely fascinating, and will change the course of research into Alzheimer's," says Julie Williams of Cardiff University, UK, who led one of two genetics studies. She says the findings "show us the prime pathways into the disease".
For the past 20 years, researchers have been trying to treat Alzheimer's by blocking the accumulation of waxy plaques in the brain, with little success. While the exact role of these plaques is still unclear, the new studies suggest that disruptions of the immune system, the way cells metabolise fat, and wear and tear on the circulatory system may be as much to blame for Alzheimer's, or perhaps even the root cause.
This could help steer Alzheimer's research towards drugs that maintain the health of immune and vascular systems, while prevention strategies might include eating a low-fat, vegetable-rich diet and exercising.
Links have recently been discovered between cognitive decline and inflammation, which is a collection of processes involving the immune and vascular systems that protect the body from a range of harmful stimuli. To explore these links, Clive Holmes of the University of Southampton, UK, measured blood levels of tumour necrosis factor alpha in 222 people with Alzheimer's. TNF-alpha is released by white blood cells during inflammation. The volunteers also took a cognitive test first when they had their blood tested, and then three more times over a six-month period.
At the end of this time, cognitive decline was four times greater in those who started out with the highest TNF-alpha levels when compared with participants who had no TNF-alpha, whose cognition remained almost stable. A rapid decline in cognitive ability was also evident in people who had routine infections or accidents such as falling over, all of which can trigger inflammation (Neurology, vol 73, p 678). Interestingly, these inflammation "events" were seldom in the brain itself, but the rest of the body and bloodstream.
Holmes says that the results in people echo earlier experiments in mice, which showed that inflammation, and particularly high concentrations of TNF-alpha in the blood, accelerated Alzheimer's-like decline and death. He found that in the mice, microglial cells, responsible for removing dead neurons and destroying infectious agents, overreacted to TNF-alpha. He speculates that this might have caused microglial cells to kill live brain cells and that this is how inflammation contributes to, or even causes, Alzheimer's in people.
Backing this idea is the discovery of three gene variants that are more common in people with Alzheimer's than in the general population. Two separate research teams were involved, one led by Williams, the other by Philippe Amouyel of the Pasteur Institute in Lille, France (Nature Genetics, DOI: link and DOI: link). Both teams scanned between 300,000 and 500,000 single letter variations of the genetic code in thousands of people with Alzheimer's.
Until now, the main gene associated with Alzheimer's has been a faulty version of apolipoprotein E. Because faulty APOE causes people to make too much beta amyloid, the substance found in the waxy plaques of people with Alzheimer's, this reinforced theories that Alzheimer's is caused by plaques.
While the new research further confirmed that APOE is the most important gene variant predicting susceptibility to Alzheimer's, it also threw up three new gene variants that are abnormally common in people with Alzheimer's.
One of these variants is in the clusterin gene that clears the brain of protein junk, including beta amyloid. It is also responsible for dampening down aspects of the immune response, including one immunological chain reaction called the complement cascade, which rids the body of unwanted cells, toxins and proteins that have been snared by antibodies. Another is a variant of the CR1 gene, also vital for controlling the complement cascade.
It is not clear yet whether the variants cause these genes to be under or over-active. But because both genes are intimately involved in controlling the immune system, the discovery of their link with Alzheimer's fits with Holmes's result, and opens up a range of alternative causes and treatments.
The normal version of CR1 helps prune synapses, the brain connections destroyed in Alzheimer's. In people with the mutated form of CR1, this process may go into overdrive and destroy too many connections. Similarly, mutant clusterin may not damp down the immune system enough, causing it to attack, not protect, the brain.
Another possibility is that both gene variants affect a person's ability to repair blood vessels. As people get older, blood vessels become more damaged, particularly in the brain. The complement cascade is involved in fixing this damage, so the CR1 and clusterin gene variants may impair the repair process.
If this is true, better cardiovascular health might guard against the damaging effects of these mutant genes - and perhaps prevent Alzheimer's, says John Hardy of University College London, a pioneer of the plaque hypothesis. "This is pushing very much on the idea that we should focus on heart fitness," he says.
Meanwhile, the third gene to be implicated in Alzheimer's was a variant of the PICALM gene, which draws fats and proteins into brain cells, and may also be active around synapses. The researchers suggest that the variant associated with Alzheimer's may cause too much fat to be drawn into cells, killing them.
Both this hypothesis and the blood vessel one are backed up by a study published last month. Nikos Scarmeas of Columbia University Medical Center in New York and colleagues found that the risk of Alzheimer's was reduced by a third in volunteers who were physically active, while those who ate a diet rich in fruit and vegetables lowered their risk by 40 per cent. Those doing both lowered their risk by a massive 60 per cent (Journal of the American Medical Association, vol 302, p 627). What's more, in January research by Deborah Gustafson of the University of Gothenberg in Sweden linked obesity to a higher risk of Alzheimer's disease.
Williams says it is time to shift the focus away from the plaques. "We need to put the immune response, inflammation and the release of fats and cholesterol at the heart of future research." Hardy is less gung-ho as he suspects the plaque hypothesis will eventually produce drugs that work. But he agrees that preventing damage to blood vessels should now be explored as an Alzheimer's strategy.
Holmes points out that there are existing drugs for rheumatoid arthritis that neutralise TNF-alpha and might be worth trying. Tantalisingly, one such drug, etanercept, may already have helped people with Alzheimer's. The results, published last year, were dismissed by many. Maybe it's time to revisit that verdict.
Plaque Drug Trials Fail
Alzheimer's has long been blamed on the fatty amyloid plaques that accumulate in the brain, but recent clinical trials suggest other processes may be at work.
Last year, Clive Holmes and his colleagues at the University of Southampton, UK, examined the brains of dead patients who'd received a vaccine that primes the immune system to attack amyloid plaques. Although the plaques had gone in most patients, in life their symptoms hadn't diminished (The Lancet, vol 372, p 216).
Also disappointing was the performance of tarenflurbil (Flurizan), a drug designed to attack plaques. Myriad Genetics of Salt Lake City, Utah, announced last year that it was suspending the $200 million trial of the drug, the largest ever of an Alzheimer's treatment, after it failed to deliver significant improvements in memory, cognition or people's ability to care for themselves.
Meanwhile, drugs targeting other processes have shown success. The most tantalising news comes from trials of dimebolin, a hayfever treatment developed decades ago in Russia. Results from a trial published last year in The Lancet (vol 372, p 207) showed that patients taking the drug scored 7 points higher in standard tests of cognitive abilities compared with those on placebo, a substantial improvement on a scale of 70. As hay fever is caused by the body's inflammation process going awry, this result chimes with gene and hospital studies published this week that suggest inflammation plays a role in Alzheimer's
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