Alzheimer’s disease has all the hallmarks of a medical problem awaiting a high-technology solution: millions of sufferers worldwide; a mysterious brain degeneration that confines its victims to a twilight world of confusion and lost memories; and a costly scientific search for a cure that has so far produced more controversy and frustration than promising leads. So it would be surprising if the destructive advance of this neurological disorder could be slowed, perhaps even stopped, with anti-inflammatory compounds related to the humble aspirin. That, though, is exactly what medical researchers in the US and Canada are trying to prove.
This summer, in the journal Neurology, Joe Rogers of the Sun Health Research Institute in Sun City, Arizona, and Pat McGeer of the University of British Columbia in Vancouver will unveil the results of an apparently promising clinical trial of an aspirin-like drug called indomethacin on Alzheimer’s patients. In the fiercely competitive world of Alzheimer’s research, the findings are likely to provoke heated debate. And it is not yet clear that any one drug could arrest all the complex symptoms of Alzheimer’s disease. But if the two neurologists are right, their ideas could revolutionise thinking about Alzheimer’s disease and perhaps other illnesses, too.
The clinical trial is based on a radical theory as to what causes brain cells to die in Alzheimer’s disease. Forget elusive viruses, the alleged hazards of aluminium and unconventional disease agents. Alzheimer’s disease, argue McGeer and Rogers, is essentially an inflammatory condition akin to rheumatoid arthritis. In other words, the neurological damage is caused by a local overheating of the immune system, in which biochemical and cellular defence mechanisms turn against the brain cells they are meant to defend.
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Already, word of the clinical trial is beginning to spread among Alzheimer’s researchers, inspiring a cautious respect for McGeer and Rogers’ work. ‘From what I understand, they have got some exciting results,’ says Zavan Khachaturian, of the the National Institute of Aging in Bethesda, Maryland. Although Khachaturian is not sure whether anti-inflammatory drugs, if effective, will do more than slow the advance of dementia, he notes the obvious advantages: ‘Imagine (Alzheimer’s patients) having only to take aspirin, or aspirin-like compounds. That would be terrific.’
A few years ago such enthusiasm would have seemed misplaced. In the late 1980s, Alzheimer’s laboratories in both academia and industry began to direct most of their efforts at unravelling the role of a peptide called beta-amyloid. That inflammation might be central to the disease was a much less fashionable avenue of research.
The beta-amyloid peptide is released by cells as a fragment of a much larger molecule, the amyloid precursor protein, or APP. No one yet knows what the normal function of APP is, but there are three good reasons for thinking the beta-amyloid peptide it releases might have something to do with Alzheimer’s dementia. First, lesions in the brains of Alzheimer’s victims typically contain a mass of dead, or dying, cells, with a clump of insoluble, aggregated beta-amyloid fibrils at the centre. Secondly, people with Down’s syndrome, who for genetic reasons produce abnormally high levels of APP, tend to develop similar kinds of lesions in the brain. And finally, over the past three years a number of teams have identified mutations in and around the APP gene which predispose people to hereditary, early onset forms of Alzheimer’s disease.
Yet none of this proves that beta-amyloid actually kills brain cells. Establishing that is proving harder than anyone imagined in the 1980s. And with researchers still locked in debate, the heresy lingers that beta-amyloid might simply be an innocent bystander – or, at any rate, not the central villain of the piece. A further complication is that the brains of Alzheimer’s patients contain not only beta-amyloid deposits but minute bundles of abnormal thread-like protein material. These so-called neurofibrillary tangles accumulate in neurons in certain parts of the brain where they may well interfere with normal neural function. Whether they are linked in any way to the beta-amyloid deposits, or indeed play any part in Alzheimer’s disease, is still unclear.
Having spent time and money galore pursuing the beta-amyloid connection, some neuroscientists and drugs companies may be understandably less than eager to embrace the news that inflammation might be just as important. For their part, however, McGeer and Rogers see no great conflict between their ideas and the beta-amyloid hypothesis. In fact, last year they took the first step towards forging a possibly vital link between beta-amyloid and inflammation. Working with researchers at the Scripps Institute in La Jolla, California, and Athena Neurosciences, a San Francisco biotechnology company, they discovered that aggregated beta-amyloid can activate a key component of the immune system, the so-called complement cascade. This chain of molecular events produces proteins that can fatally wound cells, and is normally only triggered by antibodies and when there is a need to destroy damaged or infected cells. If McGeer and Rogers are right, however, the cascade can also be triggered by beta-amyloid, precipitating the slaughter of otherwise healthy neurons.
Why deposits of beta-amyloid form in the first place is still unclear. But McGeer’s team thinks it has evidence that microglial cells, cerebral cousins of macrophages, the body’s im-munological scavengers, may be involved in producing or pro-cessing the protein. What’s more, says McGeer, injured neurons seem to produce more APP than healthy cells and hence more beta-amyloid – raising the prospect of a chain reaction. If injured neurons were to start pumping out more and more beta-amyloid, the complement cascade would become ever more active, and this in turn would injure more neurons. ‘The thing burns hotter and hotter,’ suggests McGeer, ‘until finally, it starts to destroy the surrounding tissue.’ Why Alzheimer’s disease affects some and not others is still a mystery, he acknowledges. But the essential problem is the immunological fire. ‘Our proposal,’ says McGeer, ‘is merely to cool the fire.’
Ferocious cells
Neither McGeer nor Rogers is noted for making outlandish medical claims. McGeer has been at the University of British Columbia since 1959, concentrating for much of that time on how nerve cells communicate in the brain. In the early 1980s, he and his colleagues were among the first to link Alzheimer’s dementia with the destruction of neurons that specialise in producing a neurotransmitter called acetylcholine. This quickly gave birth to the idea that a failure to produce acetylcholine is partly responsible for the some of the symptoms of the disease, particularly memory loss. Like many other researchers at the time, McGeer then began to look for ways of boosting acetylcholine levels.
But in 1984 his research took a strange twist. A technician showed him electron micrographs of what looked like viral particles in samples of brain tissue from Alzheimer’s victims. Could a slow-acting virus be the cause of Alzheimer’s disease? McGeer and his colleagues tested sample after sample of autopsied brain tissue for traces of viral genetic material, but in vain. Frustrated by this, they adopted a less direct approach. Viral infections normally elicit a specific response from the immune system: antibodies, immune cells and a variety of powerful immunological chemicals are mobilised to attack infected cells. Instead of searching for the virus itself, the researchers would look for some of these immunological ‘footprints’. ‘And that,’ remembers McGeer, ‘is when every experiment started to work.’
McGeer and his team discovered that the brain lesions found in Alzheimer’s patients are filled with microglial cells. These normally seem to play a kind of housekeeping role in the brain, disposing of neurons that have been wounded, killed or compromised by infection. But the microglial cells found in the Alzheimer’s lesions seemed to be unusually ferocious. As well as devouring neurons, they appeared to be secreting toxic proteins belonging to the complement cascade. McGeer wondered if they were also killing innocent bystander cells. Perhaps Alzheimer’s disease was not caused by a virus after all, but by certain localised elements of the immune system running amok.
If all this were true, epidemiological evidence should both confirm it and point to a therapy. More specifically, people who take anti-inflammatory drugs on a long-term basis, such as rheumatoid arthritis patients, should be unusually resistant to Alzheimer’s disease.
To test this hypothesis, McGeer teamed up with Rogers, who had independently been investigating the role of inflammation in Alzheimer’s disease. In 1989, they examined the hospital records of some 12 000 patients in the US and Canada who had suffered from Alzheimer’s disease or rheumatoid arthritis. It seemed that an unusually small number of these patients had been diagnosed as having both diseases – exactly as one would expect if anti-inflammatory drugs prevented, or slowed, the progress of Alzheimer’s disease. McGeer and Rogers soon discovered that doctors in London had reported a similar observation in the British Journal of Rheumatology, postulating a genetic link between susceptibility to arthritis and resistance to Alzheimer’s disease.
The leprosy connection
A further piece of evidence came from Japan, where a colleague of McGeer’s had noted an unusually low incidence of dementia in a leper colony on the island of Nagashima. This prompted McGeer and a group of Japanese researchers to examine the medical records of some 4000 Japanese leprosy patients, with startling results. Patients who had been taking dapsone – the leprosy drug of choice in Japan – had a significantly lower incidence of dementia (2.9 per cent) than those who had not been taking the drug (6.25 per cent). What’s more, the incidence of dementia among patients who had taken the drug intermittently in the previous five years fell squarely between these figures (4.83 per cent), suggesting a dose-response effect. Dapsone is not only a powerful antibiotic, but is also an effective anti-inflammatory drug. Indeed, it has been prescribed for a number of autoimmune disorders including rheumatoid arthritis.
Another group of Japanese researchers, hearing about McGeer’s dapsone study, analysed the autopsied brains of 16 leprosy patients. When most people age, their brains normally develop a few lesions, or ‘senile plaques’, that are similar to those in Alzheimer’s patients. But in the brains of the leprosy patients, such plaques were conspicuously absent.
By the time McGeer’s dapsone study was published in the journal Dementia in the summer of 1992, Rogers had nearly completed a preliminary clinical trial of indomethacin, a drug which curbs inflammation by blocking the action of an enzyme called cyclo-oxygenase. Indomethacin was chosen because it is much better than other drugs of this type at crossing the blood-brain barrier. In all, 44 patients with early-stage dementia were enrolled, half of whom received indomethacin, and half a placebo. Using four standard tests of intelligence and recall, doctors measured the severity of each patient’s symptoms of dementia at the start of the trial and after six months. In two of these tests, the indomethacin group suffered no deterioration during the trial period.
The big drawback with indomethacin is its severe gastro-intestinal side-effects, which can be much worse than aspirin and most other anti-inflammatory drugs. Because of this, many patients were forced to drop out; by the end of the trial only 14 patients were still receiving indomethacin. But the placebo group suffered drop-outs, too. ‘We lost about 20 per cent of our placebo patients because they went downhill, behaviourally, so much that they wouldn’t take medicine or sit for the test any more,’ says Rogers. ‘That didn’t happen with the indomethacin patients. Which is interesting.’
Rogers and McGeer emphasise that the trial is too small to prove the efficacy of indomethacin as a treatment for Alzheimer’s disease. But if its results are confirmed in a larger trial, they say, the study will greatly strengthen the notion that inflammation plays an important part in Alzheimer’s disease.
For the moment, however, most Alzheimer’s researchers are still preoccupied with the beta-amyloid protein. Since the late 1980s, more than a dozen major pharmaceuticals companies, including Upjohn, Bristol-Myers Squibb Pharmaceuticals, and Merck Sharp & Dohme, have joined the multibillion-dollar race to find drugs capable of blocking the production of beta-amyloid. Before cells can release beta-amyloid, it must be cut loose from the rest of the APP protein by an enzyme. Thwarting this enzyme is now the main goal of researchers at Athena Neurosciences, which, with backing from the drugs giant Eli Lilly , has built up one of the world’s largest programmes of research into Alzheimer’s disease. Ivan Lieberburg, who heads this programme, says that his scientists have identified the enzyme and, more importantly, have found several compounds which block its activity in the test tube. Lieberburg hopes to have at least one of these beta-amyloid blockers in clinical trials by early 1995.
Despite such apparent successes, however, the beta-amyloid hypothesis has recently experienced some setbacks. The first stems from efforts to make a mouse ‘model’ of Alzheimer’s disease, which would be a boon to drugs testers. In 1991, three teams succeeded in genetically engineering mice to overproduce APP in their brain cells. One of these teams claimed that their transgenic mice developed brain lesions similar to those found in Alzheimer’s patients. For many, this was proof, if any were needed, that APP causes Alzheimer’s disease by unleashing beta-amyloid on the brain. It seemed that all that remained was to find out how beta-amyloid kills brain cells.
But in March of last year, the paper was retracted from Nature, after its authors were unable to replicate their earlier findings. What’s more, there were calls for a fraud investigation, following allegations that photographs purporting to show brain damage in transgenic mice were actually photographs of brains autopsied from Alzheimer’s patients.
Within months came another challenge to the beta-amyloid hypothesis. Up until last year, most researchers had assumed that beta-amyloid is only produced when something goes wrong with the way APP is processed in cells. But in September and October came evidence to the contrary. Three research teams, led by scientists at Harvard University, Athena Neurosciences and Case Western Reserve University in Ohio, discovered that a soluble form of the beta-amyloid peptide – that is, a form which does not aggregate into clumps of fibrils – is produced by healthy cells. Far from being an exclusive ‘marker’ for Alzheimer’s disease, beta-amyloid (or at least one form of it) could also be detected in the spinal fluids and bloodstreams of perfectly healthy people. This by no means demolished the idea that beta-amyloid is involved in Alzheimer’s disease, since the disease could still be caused by unusually high levels of beta-amyloid or faulty processing of the peptide by cells. But it did complicate the picture significantly.
The most important controversy, however, has centred on beta-amyloid’s guilt (or innocence) as a neurotoxin. In the summer of 1990, the issue looked settled. Based on experiments with a specific fragment of beta-amyloid, a team led by Bruce Yankner at Harvard University claimed that beta-amyloid could indeed kill neurons provided the neurons had stopped dividing. But subsequently, several respected laboratories reported difficulties replicating this result, and for a time the debate became heated. Now the tide seems to be turning in Yankner’s favour. The key, argues Dennis Selkoe, who runs another Alzheimer’s laboratory at Harvard, is that beta-amyloid only becomes toxic after it has aggregated into insoluble fibrils. ‘People have had real problems reproducing in vitro toxicity by just adding beta-peptide in solution to media,’ he admits. ‘But if they allow the peptide to aggregate, it looks like it does produce some local toxicity when added to cultured cells.’
Toxic leap
McGeer and Rogers are willing to concede that beta-amyloid can kill neurons directly, but think that most of the damage is caused by the peptide’s immunological effects – specifically, its ability to activate the complement cascade. Our unpublished results show that ‘when immune factors are present, the toxicity of beta-amyloid jumps tremendously,’ says Rogers. ‘So beta-amyloid is probably mildly toxic by itself, and probably very toxic when it has attracted the immune system.’
Proponents of the beta-amyloid hypothesis tend to believe the reverse is true – that beta-amyloid itself does most of the cell killing. But most acknowledge that there could still be a role for anti-inflammatory drugs in slowing the progress of Alz-heimer’s disease. ‘I think that has to be considered as a possibility,’ says Yankner. ‘So I’m on the fence about that right now.’
Lieberburg says his company has a foot in both camps. ‘There is good reason to suspect that inflammation is part and parcel of Alzheimer’s disease, and contributes to the ongoing dementia that the patient experiences.’ He notes that the side effects of indomethacin will probably make it unsuitable for widespread use in elderly patients, but he concedes that the results from the clinical trial are ‘very interesting’ and congratulates McGeer and Rogers for forcing open a new avenue of Alzheimer’s research.
‘It’s people like Joe Rogers and Pat McGeer who continued to hammer away on this inflammation issue and to say, ‘Look, this is right under your noses here; this looks like chronic arthritis of the brain – why do you continue to ignore this?” In fact, confides Lieberburg, Athena has been pursuing its own secret anti-inflammatory programme for the past four years, and has been screening for a drug which can penetrate the blood-brain barrier while having better anti-inflammatory properties and fewer side-effects than indomethacin.
Look, no antibodies
McGeer and Rogers, meanwhile, have obtained a US patent on the use of drugs like indomethacin to treat Alzheimer’s disease. Pharmaceuticals companies, though expressing interest in their work – ‘my calendar this spring has been filled with visits to drugs companies,’ says Rogers – have not yet been willing to help the two researchers through the long and expensive process of winning approval for indomethacin as an Alzheimer’s treatment from the US Food and Drug Agency. But the two are forging ahead anyway. Rogers, with financial support from local doctors in Sun City and the Sun Health Research Institute, has begun a new clinical trial of indo-methacin, this time in 120 Alzheimer’s patients.
The legacy of McGeer and Rogers’ research might extend well beyond Alzheimer’s disease. McGeer believes that the way in which beta-amyloid provokes the immune system, to such fatal effect, may hold an important lesson for researchers investigating other autoimmune diseases. According to the conventional view, autoimmunity occurs when the the immune system mistakenly reacts to specific proteins, or antigens, as though they were foreign. As a result, the immune system produces antibodies and immune cells that are directed against some of the body’s own antigens.
In the case of Alzheimer’s disease, however, and perhaps other autoimmune conditions, McGeer envisions something different happening. Instead of stimulating the production of antibodies and immune cells that home in on specific antigens, beta-amyloid clumps seem to activate the immune system at a deeper level. The complement cascade is normally stimulated by antibodies. But beta-amyloid seems to ‘short-circuit’ this re-quirement, stimulating the cascade without the aid of antibodies. McGeer argues that just because one or two automimmune diseases – such as myasthenia gravis, a muscle weakening disease – are known to be triggered by a specific antigen, we shouldn’t assume that the rest work the same way. ‘No one has been able, for example, to define antigens in rheumatoid arthritis, Behcet’s disease, temporal arteritis,’ he says. ‘I think there’s a missing link here, and quite a big one’.
