Diary of an Alzheimer's scientist
Thursday, 6 July 2000
I'm on flight CO 4421, about to land at Dulles Airport. I've come to Washington, along with 5,000 other Alzheimer's scientists, to attend our biennial jamboree, the World Alzheimer Congress. At the last such event, in Amsterdam in 1998, I was hugely impressed by the progress that had been made in just two years. I know that as much progress has been made in these last two years. Yet, the sad fact is we still don't know what causes this tragic disease.
If you've watched a close friend or relative being taken away by Alzheimer's over 5 or 6 years or so, you'll understand the extent of the tragedy. Gradually they're robbed of everything that makes them human: their memory, their personality, their personal relations, their manual skills, their independence, their dignity. Their carer, the spouse or daughter, for instance, cannot but be heavily marked by the unremitting ordeal. The cost to the world's health services runs to billions of pounds a year. Research has made dramatic progress. Yet, the big questions remain unanswered.
Why is that? Alzheimer's is the most common form of old age dementia, accounting for about two thirds of cases. That means over four million people currently have Alzheimer's in Europe alone. With the ageing population, that figure could rise dramatically. Now, medical science has made wonderful progress in understanding single-cause diseases, where the main culprit is, for instance, a virus or a single gene. But Alzheimer's, apart from some rare early-onset forms, is a complex disease, like heart disease and also like many other illnesses of the brain. I mean that Alzheimer's results from the interaction of many factors: genetic, environmental and related to life-style. Some genes may make their carriers more susceptible. But there is also some evidence, for example, that both physical and mental activity are to some extent protective. Many factors play a part and unpicking their interacting roles has so far defeated our best efforts, as in other complex diseases.
Surely though, senility is an inevitable feature of the human condition; it is the seventh age of man after all, the "second childishness, and mere oblivion, sans teeth, sans eyes, sans taste, sans everything." Till recently, some scientists believed in that inevitability. Alzheimer's is just an extension of ageing, surely? Not so, as shown a few years ago by my colleagues in OPTIMA, the Oxford Project to Investigate Memory and Ageing. Kim Jobst and David Smith used CT scans to measure the width of a brain structure called the medial temporal lobe (MTL). They found that all of us show some slight atrophy of the MTL in old age, a decline rate of about 11/2 % a year. But something dramatic happens to some people: suddenly their MTL starts to waste away 10 times faster and practically disappears in 6 or 7 years. So Alzheimer's is indeed a disease. It is strongly associated with ageing, but not the inevitable consequence thereof. If it is a disease, then we can discover its causes, and if we know the causes and can establish who is at risk, we may prevent the onset. Ah, to prevent the onset! - that "catastrophic event," as David Smith called it, an event that precedes an irreversible decline. What triggers that catastrophe? We don't know.
I think most Alzheimer's scientists would agree that the inexorable decline in the faculties of a sufferer is largely due to a massive loss of nerve cells, known as neurones, and their connections. But what kills the neurones? Are they poisoned by substances around them, perhaps in senile plaques, the defining lesions of Alzheimer's? Or are they gradually destroyed from within by a mass of twisted filaments or tangles that also feature in Alzheimer's? Or are they programmed to commit suicide in the abnormal environment of the Alzheimer's brain? There is evidence for each of those processes.
These are some of the questions in my mind as our plane comes in to land at Dulles. What causes Alzheimer's? What triggers its onset? What kills the neurones? And what genes are involved and how do they work? And what about therapy? Currently approved treatments do nothing to delay the progress of the disease. They have only a short-term effect on symptoms and only in some patients. Recent drug trials have been very disappointing; most have failed. But those were treatment trials, which are cheaper to run than prevention trials. The best hope lies in prevention, which implies the need to predict who is at risk. Let's see if any really good ideas emerge from the congress. Will I get answers to any of these questions?
Saturday, 8 July 2000
Early morning walks are a great pleasure in this elegant, embassy district of Washington. It is my first time here and I am enchanted by the trees of Washington, lining almost every street, in lavish variety, some in flower in July, some hiding noisy birds at this hour. Below are neatly laid out gardens, with little notices such as 'Please ask your dog to fertilize your garden - thanks', and with squirrels just like the ones that do so much damage in my Sussex garden. I pass a line of tall ginkgo trees and am reminded that ginkgo biloba is thought to protect a little against the early stages of Alzheimer's. But what triggers the disease?
One possible trigger is brain inflammation. You'll be familiar with inflammation as a rapid, defensive reaction of our bodies to injury or infection, a reaction that soon attracts powerful immune cells to the site. But the brain is a very special site, separated from the rest of the body by the blood-brain barrier. Yet inflammation can occur in the brain. Patrolling immune cells, the microglia, are found there and other immune cells can cross the blood-brain barrier in certain circumstances; though most scientists doubt if they do in Alzheimer's and therefore debate whether it can be called an inflammatory disease. Still, the Alzheimer's brain has many signs of inflammatory events. Large numbers of 'activated' microglia are found, especially around senile plaques, 'activated' meaning 'primed for action'. The plaques contain many of the proteins involved in inflammation. Raised levels of inflammatory chemicals called cytokines are also found in the Alzheimer's brain. But is all this inflammatory activity a cause or a result of the disease process? Or could it be both, part of a vicious circle?
In old age, our immune systems are weakened and may function aberrantly. Could it be that some insult, an infection or a minor head blow perhaps, that would not have bothered us in youth might have malign consequences in old age? - might provoke an over-reaction of the immune system, that damages some irreplaceable neurones and sets in motion that dark train that leads to 'mere oblivion'? Or does inflammation board the train later, once it has started its unstoppable, downhill run? Many Alzheimer's scientists consider that at least inflammation contributes to the journey, whether as driver, assistant or passenger. They are encouraged by surveys that suggest that people on anti-inflammatory medication, for rheumatoid arthritis, for instance, may be somewhat protected against Alzheimer's. But the hypothesis is hard to prove. That is partly because, in spite of remarkable progress in brain scanning, that "catastrophic event", the onset of Alzheimer's, has not been witnessed. Most evidence comes from post-mortems, where it is not the onset that is normally seen, but more often the end stage of the disease and the debris of past inflammatory events.
I've spent the last two days listening to talks on this theme, at the conference on 'Neuroinflammation in Alzheimer's Disease' that precedes the main congress. An important component of inflammation is a group of about 30 proteins called complement. These complement proteins activate each other in turn: an inflammatory sequence that is crucial to our bodies'defence. The final members of this protein sequence join up to form the membrane attack complex (or MAC). These MACs attach to a cell, punching holes in its membrane, so that calcium streams in, cellular components leak out and the cell dies. This is bad news for invading bacteria. But what of our own cells? It has been said that we have enough complement in circulation to destroy every cell in our bodies in five minutes. Fortunately, our cells are protected by various complement inhibitory factors that keep the killers in check. Certain viruses too have learnt to hold them off. But what starts the process? There are various switches, such as antibodies attached to foreign substances. A crucial discovery was made in 1992 by Joseph Rogers' group at the Sun Health Research Institute with Patrick McGeer of the University of British Columbia and others. They found that the core material of senile plaques, beta amyloid, is one of the rare substances that can activate the complement sequence by itself, even without any antibody. Is this how the vicious circle starts? A little pathology provokes inflammation, which in turn causes more damage?
Yesterday I heard several talks on the complement system in Alzheimer's. It seems that, though high levels of complement proteins are found in Alzheimer's brain, numbers of inhibitory factors are not so increased. Speakers such as Piet Eikelenboom of Vrije University, Amsterdam pointed out that this imbalance may seriously damage neurones in Alzheimer's. The case is unproven, however. Only a few of the many inhibitory factors have so far been examined in Alzheimer's brain. Still, the image is compelling. The killers are unleashed. The pack of Rottweilers turn on their owners.
Could anti-inflammatory drugs prevent Alzheimer's? It might seem to follow, yet nothing is simple with this disease. Steroids are powerful anti-inflammatories, yet the recent trial of a steroid, prednisone, completely failed. Ian Mackenzie of Vancouver General Hospital and David Munoz of University Hospital, London, Ontario might say they would have told us so. They have looked at the effects on the brains of old people of two classes of anti-inflammatories: steroids and non-steroidal anti-inflammatory drugs (known as NSAIDs, pronounced N-seds). They presented their results at this conference. Briefly, though neither steroids nor NSAIDs prevent the formation of plaques and tangles, NSAIDs, but not steroids, do reduce the activation of microglia. Indeed, a small trial of an NSAID, indomethacin, back in 1993, by Rogers and McGeer and colleagues, showed some promise. So are microglia the culprits? As is typical in Alzheimer's, the answer is yes and no. These powerful immune cells can play the nurse or liquidator. They listen to signals from sick neurones and may respond with healing substances. But if the signals are too strong and the patient's condition is deemed terminal, the nurse may opt for euthanasia. Microglia may also have a role in degrading plaques. In the drama of Alzheimer's, the good and bad boys keep swapping places. Is inflammation hero or villain? The short answer is that, though it can be beneficial, chronic inflammation, as seen in Alzheimer's, is likely to damage neurones. Anti-inflammatory drugs are worth trying, but it may not be easy to find the one with just the right pattern of actions.
Sunday, 9 July 2000
During the next five days, I expect to hear a great deal about proteins (and you will hear a little). As you may remember, proteins are very large molecules that do most of the really clever things in our bodies. For instance, the enzymes that organise the vital chemical reactions and the transporters that move the products around our bodies are proteins. You won't be surprised then to hear that misbehaving proteins play the main roles in Alzheimer's pathology. Two proteins that have become famous for their aberrant behaviour in Alzheimer's are tau and the beta amyloid peptide (a peptide is like a very small protein or part of a larger one).
Most of what we know about the disease process comes from an immense amount of painstaking work by neuropathologists over many years. They look at thin slices of Alzheimer's brain, carefully stained to show the features of interest. The microscope reveals a marvellous pattern of interacting cells and lesions. Some of the neurones may be stained dark, showing that they are clogged up with tangles. Here and there are large, round blobs or plaques, some containing thin neuronal processes, known as neurites. The progression of the disease may be measured in part by the number of tangles or of neuritic plaques (non-neuritic plaques are often found even in healthy, aged brains). Each of those two measures has been correlated to some extent with patients' decline in mental faculties.
Though many of the protein suspects of Alzheimer's pathology are found in these senile plaques, the central core of neuritic plaques is largely composed of long threads or fibrils of beta amyloid peptide. This fibrillar beta amyloid can be toxic to neurones. Hence the amyloid hypothesis of Alzheimer's. On the other hand, tangles correlate still better with mental decline and a tangled neurone is clearly on its way out. Tangles represent the breakdown of the neurone's internal skeleton. A vital component of that skeleton is the tau protein. In Alzheimer's, an abnormal or 'hyperphosphorylated' form of tau fails to bind to the skeleton. The skeleton breaks down. The neurone dies. So are these lesions causal or do they merely represent the debris of the disease process? If they are causal, which one is primary, plaques or tangles? These are among the great unresolved debates of Alzheimer's. Will this congress bring us closer to a resolution?
What exactly is the role of beta amyloid in the disease? That question has generated more heat over the years than any other topic in Alzheimer's research. The problem is this. On the one hand, there are three genes that cause the diseases at an early age (30 to 60). Each of these genes results in raised brain levels of a particular type of beta amyloid that is more prone to form fibrillar deposits. The link between beta amyloid and the disease in these, admittedly rare, cases is compelling. Further, fibrillar amyloid has been shown to poison neurones, at least in the laboratory. Similar deposits or plaques are found in all cases of Alzheimer's and are therefore presumed to be causal by the supporters of the amyloid hypothesis. In other words, amyloid plaques are primary and other pathology, such as tangles, as well as the disease symptoms, all flow from these primary lesions. On the other hand, plenty of alert, healthy old people have amyloid deposits in their brains, though usually not of the fibrillar sort. Also in Alzheimer's, measures of amyloid load do not correlate well with either neuronal loss or with disease duration or with the patient's symptoms. Numbers of tangles, for instance, correlate better with mental decline.
Every Alzheimer's scientist has his or her own way of resolving this amyloid paradox. Such resolutions range from suggesting that amyloid plaques are the mere result of the disease process or at best secondary factors in its development, to putting the blame on particular types of amyloid. Beta amyloid has many personalities. These include a soluble form found in our body fluids, an insoluble form seen in the possibly harmless, diffuse deposits of both the healthy aged and Alzheimer's patients, and also the fibrillar form found in the dense, neuritic plaques that are characteristic of Alzheimer's. Over the years, the amyloid hypothesis has proved as changeable as amyloid itself.
Colin Masters of Melbourne University was one of the first proponents of the amyloid hypothesis. Today he made a new, controversial proposal. He now considers that it is not the fibrillar, insoluble form, but rather a particular type of soluble amyloid that is the chief culprit. Though this soluble form represents a small fraction of the total amyloid in the brains of the elderly, Masters' group have found that its levels correlate well with the severity of Alzheimer's: the more soluble amyloid in the brain, the worse the disease, they claim. They are now testing whether this type of soluble amyloid poisons neurones. They are already talking of treatment to clear it from the brain...
Monday, 10 July 2000
I wake up still confused about amyloid - if you are, join us. Bradley Hyman, of Massachusetts General Hospital, is a man whose judgement I would back on many issues in Alzheimer's. I will go to his talk this morning. He has been addressing the issue: do amyloid plaques kill neurones? His group have been counting neurones around plaques in the brains of mice. Mice don't get Alzheimer's, but their genes can be manipulated to give their brains a heavy load of amyloid. Hyman now reports that they have found neurone-free holes around a particular type of plaque in these mouse brains. These are large, dense plaques that can be stained with a chemical called thioflavine S. In Alzheimer's brain, such plaques typically contain fibrillar amyloid and sick neurites. How do they kill neurones? Hyman points out that these are also the plaques most likely to attract activated microglia. Ah, inflammation again.
I am sure I will hear more of the amyloid hypothesis this week, but just now I need a new focus. Genetics is a subject that arouses passion among Alzheimer's scientists. Remarks at
today's session included, "Your refusal to reveal your location [ie of their new gene] is totally unacceptable" and "Keep your derogatory remarks to yourself...[then, under his breath] Bastard!"
What is so inflammatory about Alzheimer's genetics? After all, apart from some rare early-onset forms of the disease, Alzheimer's is not a hereditary illness in the traditional sense, like haemophilia or sickle-cell anaemia or Huntingdon's disease. In those cases, if you are unlucky enough to inherit a dud version of the gene, or in some diseases two dud copies, then you will get the disease. The gene is causative. In contrast, there are no causative genes for late-onset Alzheimer's (by 'late' I mean over 65), only a number of genes that increase the risk, that make carriers of the gene more susceptible.
There is good evidence of a strong genetic component, probably a number of these 'susceptibility genes', in Alzheimer's. Yet, in spite of considerable efforts world-wide, only one such gene has been firmly established. That is the gene for apolipoprotein E, commonly known as apo E. This gene comes in three main versions, APOE2 (pronounced apo-E2), APOE3 and APOE4. APOE3 is the most common and APOE4 is a risk factor for Alzheimer's. All of us have two copies of the apo E gene. You might have two copies of APOE3, for instance, and I might have one of APOE3 and one of APOE4 (though I don't know - like nearly all Alzheimer's scientists, I have not asked to be tested). Just over 25% of the white population carry APOE4, but up to 60% of Alzheimer's sufferers have it. From that, we may calculate that carrying APOE4 increases your risk by about four times. That is what is meant by a genetic association. On the other hand, 40% of Alzheimer's patients don't carry APOE4, and there are good reasons to believe there are other susceptibility genes yet to be found, perhaps as important as APOE4. The APOE4 connection with Alzheimer's was discovered in 1993 by Allen Roses' group at Duke University and has since been confirmed worldwide. Many other susceptibility genes have since been proposed and some may indeed be weak risk factors for Alzheimer's. Claims are now made almost monthly. But none have shown the staying power of APOE4.
Why is all this important? After all, I said just now that few Alzheimer's scientists have been tested for APOE4. This is because they know nothing can be done about the risk as yet. But is gene therapy for Alzheimer's around the corner? Hardly. So why the intense search for Alzheimer's genes? The recent completion of the first draft of the human genome will have reminded you why genes are important. Each gene is the code or blueprint from which a protein is built. The APOE gene codes for the apo E protein, which is a transporter of fats. You will remember that aberrant proteins play the main roles in Alzheimer's pathology. Understanding the genetics should teach us then how the proteins behave in Alzheimer's and ultimately therefore its causes...
You will see then why I awaited the various sessions on genetics with a certain throb of curiosity. But I am sorry to report that the frustrations of the last few years continue. Let me give an example. A gene called alpha-2 macroglobulin (A2M for short) looked a promising candidate for several reasons. Then Rudolph Tanzi and Deborah Blacker's group at Massachusetts General Hospital claimed a strong association for it with late onset Alzheimer's about two years ago. Since then, many groups have tried to replicate that result and most have failed. Yesterday Cornelia van Duijn of Erasmus University, Rotterdam reported on her group's thorough study, as well as an analysis of all previous reports. The outcome? A2M shows no association at all with late-onset Alzheimer's in Caucasians, though there may be one in Orientals and there is just a hint now of one with early, instead of late-onset Alzheimer's in Caucasians. Today Tanzi argued that the failure was not in the original discovery, but in the case-control methods of the dissenting studies, as opposed to his preferred family-based methods. But case-control studies are prone to false positives, while family studies can miss true associations. In this example, it would be the opposite.
The A2M story is only slightly worse than typical. Since the APOE4 discovery, all the exciting genetic 'breakthroughs' have ultimately proved disappointing. The first discovery may be followed by a few replications, but usually more failures. Be cautious of breakthroughs. All this contrasts with APOE4, whose association with Alzheimer's has been replicated by practically every group in the world, at least in Caucasians and Orientals, though probably not in Africans. Yet, seven years after that discovery, the reason for that association is still not clearly known, though several, highly plausible hypotheses have been propounded. Donald Price remarked at this congress that 'as soon as a gene is defined, the pace of research quickens.' That may be true, but it is a long, tortuous path to understanding.
I don't want to imply that there are no promising candidate genes about. There are, such as the inflammatory gene, interleukin-1, whose candidature was first proposed by Luigi Grimaldi and colleagues from Milan and Bologna, and has since been supported by others. But for many of these genes, it is still early days. My hunch is that there is another APOE4 out there waiting to be discovered...
In the evening we wander through Adams Morgan and enjoy the cross-cultural scene: 'Latino Coneccion Store', 'Neighbours' Consejo', 'Casa Africana', 'Kung Fu Pizza' and 'Guinness brings the sound of Reggae'. Talking to practically anyone we care to, I reflect on my Britishness back home. On the 7.27 from Paddington, if I've decided I've got 45 minutes to read these papers, heaven help any friendly American who wants to talk to me. Turning back at the 'Scottish Rite Center for Childhood Disorders', we pass the 8th Day Church and the Christ House, where we chat to an old, black, cancer-ridden resident, having a quiet smoke on the front doorstep. "When I came here three months ago," he says, "I was sure the Devil would soon rear his head, but so far I've only seen God."
Tuesday, 11 July 2000
I walk across Connecticut Avenue, dodging the cabs and thinking about the death of neurones. How do neurones die in Alzheimer's? In several ways, it seems. Some are destroyed by the tangles that grow inside them. Some may be poisoned; the beta amyloid peptide is a strong suspect. Others may be irreparably damaged by inflammation. But there is increasing evidence that some commit suicide: programmed cell death, it is called, or apoptosis (the second 'p' is silent).
Why should neurones kill themselves? It is known that many do during the early
development of the brain when an excess of neurones is produced; those whose
growing processes fail to reach their targets in the brain are eliminated. Could it be
that in Alzheimer's, surviving neurones seek to compensate for the loss of their
fellows and, to do so, revert to a developmental stage? One of my colleagues in
OPTIMA, Zsuzsa Nagy, shocked some scientists by suggesting that in Alzheimer's,
some neurones reenter the cell cycle. What does that mean? The cell cycle is the
route cells take to replicate themselves. At the end of the cycle, they divide and form
two daughter cells. But mature neurones don't divide. We all know that! That is
why throughout our lives we slowly lose neurones, we don't gain new ones.
Neurones reentering the cell cycle? What heresy! But Zsuzsa Nagy produced good
evidence that certain key components of the cell cycle are indeed switched on in
Alzheimer's brains, but not, or less so, in healthy elderly brains. What is more, a strong
suicide clue is found in those neurones: the death-protein, Bax, a signpost on the path
that leads to apoptosis. Similar evidence has been found by other scientists, such as
Thomas Arendt of Leipzig.
What is going on? It seems that in Alzheimer's, certain vulnerable neurones attempt to reenter the cell cycle, go too far to escape the cycle, but fail to complete it. In their failure, they are left with two options: slow death by internal strangulation by tangles, or apoptosis. The death programme is switched on...
Apoptosis attracts increasing attention from Alzheimer's scientists these days, though the cell cycle hypothesis is still a minority interest. But Zsuzsa Nagy's ideas received further support yesterday from Paul Coleman of Rochester University. Different genes are switched on ( to make proteins) at distinct times in the various tissues of our bodies. Coleman has been looking at which genes are particularly expressed in Alzheimer's. Prominent on his list are cell cycle genes.
Why are some neurones in certain brain regions vulnerable to apoptosis or to tangles, while others are not? Again, we don't have full answers, but there are marked regional differences. A vulnerable region is the hippocampus, which is important for memory. Mark West of Aarhus University in Denmark has been counting neurones in five parts of the hippocampus. He confirms that we all lose some neurones in ageing. No surprise. But there is one hippocampal region, the CA1, where little or no loss in ageing contrasts with massive loss in Alzheimer's. This is further evidence that Alzheimer's is a true disease, quite distinct from normal ageing.
Today I've followed sessions from 8:30am to 7:00pm. Five days down and two to go. There are over 1,300 presentations of various sorts at this congress. Though I obviously will only have experienced a fraction of them, I will still have had over 8 hours a day of dense input for 7 days. These conferences are an amazing opportunity to get right up-to-date on so many aspects of Alzheimer's: neuropathology, genetics, epidemiology, treatment and so on. I'll probably go out on a high. But will my neurones survive? This evening we are all invited to the Corcoran Gallery by Janssen-Cilag. The Norman Rockwell paintings prove an excellent antidote.
Wednesday, 12 July 2000
In the early days of Alzheimer's research, several scientists seriously considered infection as a possible cause. But they found nothing of note and the proposal has been largely dropped. Recently the idea has come up again, specifically that persistent, latent infection could be a cause. By latent, I mean that the pathogen is dormant, not replicating and therefore very hard to detect. Most of us, for example, are permanently infected by herpes simplex virus type 1 (or HSV1). The virus lies dormant until we get a cold, for instance, when it reactivates, causing cold sores. That infection is in the periphery of the brain and largely harmless. Recently, however, Ruth Itzhaki of UMIST, Manchester reported that in some people HSV1 gets into the brain itself. Those people are more prone to Alzheimer's, though only if they also carry the APOE4 gene. Itzhaki has now described an Alzheimer's association with another herpes virus, HSV6. She suggests that periodical reactivation of these viruses in the brain may cause the damage.
Now, to most scientists' surprise, a bacterial infection has also been implicated. The bacteria are chlamydia pneumonia, which are known to cause bronchitis and pneumonia. Surely they don't also get into the brain and cause Alzheimer's? In 1998, Brian Balin and Alan Hudson's group at Allegheny University of the Health Sciences provided the evidence, which however was not replicated by two other groups. Today James Mahony of McMaster University in Canada presented similar results to Balin's. He believes the other groups' failures were precisely because this is a latent infection. There are very few bacteria, which are hard to detect. The bacteria hide equally from our immune systems and from researchers. But a latent infection is harmless, surely? Well, why is it latent? Perhaps because activated microglia are keeping it at bay. Activated microglia may attack bacteria, but they can also harm neurones. Inflammation again.
I must add that the infection hypothesis remains highly controversial, but I find it intriguing.
There is a gala reception tonight, but I didn't put myself down for it. Networking is all very well, but at my age and level of deafness, you can't actually hear what your immediate neighbour is saying at these functions. A quiet dinner with Rosa Maria at our local Japanese restaurant is a better idea. On the way, we find it is late closing at the Phillips Collection and go in. We are lucky enough to coincide with a small exhibition of superb Whistler lithographs. We chat to the owner of that collection, Steven Block, and arrange to meet him when he brings his Whistlers to England shortly.
Thursday, 13 July 2000
Today is the last day of the Congress, so what is the biggest story of the week? Perhaps the anti-amyloid vaccine of Elan Corporation, reported last year in Nature and described on Tuesday by Dale Schenk. It should be noted in passing that other groups have produced similar vaccines, including Beka Solomon's of Tel Aviv University and Dennis Selkoe's of Harvard Medical School, the latter vaccine in the form of a nasal spray. They too reported this week. What is an anti-amyloid vaccine? We think of vaccines as protection against infections, for instance, viral. But in principle, an immune response may be induced against other things in our bodies, such as cancer cells. A vaccine against a naturally occurring protein is something new, however. Elan have tried it on plaque-prone mice. Amyloid accumulation is effectively prevented and even some prior deposits are cleared. They are now doing safety trials on American and British patients with mild to moderate Alzheimer's. Early results are encouraging, we gather.
All this raises questions. Could the vaccine provoke a dangerous, autoimmune or inflammatory reaction? Not so far, apparently. Will clearing amyloid stop the disease? Selkoe, a long-time devotee of the amyloid hypothesis, was reported this week in USA Today thus: "I'm so convinced that amyloid is the main bad guy in Alzheimer's, I would take it for granted that if the amyloid went down, the mouse would learn better." Whether or not he is right, there is another question. Though the vaccine may remove amyloid in mice, will it do so in people? As was said this week in another medical context (by Wayne Koff, reported in USA Today): "They say mice lie and monkeys don't tell the truth. We'll need human trials to know for sure." Perhaps at last we really will know for sure...
Alzheimer's research is a race against an epidemic. It is estimated that, if not struck down by other causes, half of us would be demented by the age of 100. As the other causes of death diminish, more and more will succumb to this dreadful disease. Its incidence doubles with every 5 years of age over 65. That means that postponing onset by 5 years would halve the prevalence. The stakes are high.
Friday, 14 July 2000
I must get this dispatch to the Times. Then I'm off to the mountains with Rosa Maria for a couple of days. I plan to rest my shattered neurones after the sustained bombardment of the last week. I hope the World Alzheimer Congress doesn't count as a 'catastrophic event'.