杏吧原创

Attempts to treat the world鈥檚 most common form of dementia may have been attacking its symptoms, not its root cause

I HAVE lost myself,鈥� cried Auguste Deter to her physician. Deter was trying to write her name, scrawling 鈥淢rs鈥� in a spidery script, only to forget the rest every time.

鈥淲hat are you eating?鈥� the doctor asked Deter on her second day at the hospital for the mentally ill in Frankfurt, Germany, as the confused 51-year-old lunched on cauliflower and pork. 鈥淧otatoes,鈥� she replied.

That was in 1901. When Deter died five years later, an autopsy revealed that her brain was riddled with strange tangles and plaques of a fibrous material containing the remnants of dead brain cells. She became the first described case of a form of dementia now known by the name of her doctor 鈥� one Alois Alzheimer.

Over a century later, research into Alzheimer鈥檚 disease still revolves around efforts to understand those mysterious plaques and tangles. Despite decades of work, no effective treatment exists, never mind a cure. The world鈥檚 population is ageing, so that search is becoming more urgent. Alzheimer鈥檚 disease is now recognised as the most common form of dementia, with over 25 million people living with the disease worldwide, and that number is expected to pass 100 million by 2050 (see diagram). Yet today, even definitively diagnosing the disease can still only be done at autopsy.

The situation is starting to change, however. Thanks to a new imaging technique, the plaques can now be seen in the brains of living people. Not only could this allow early diagnosis, it is helping to overturn the long-standing orthodoxy over the causes of Alzheimer鈥檚 and paving the way for effective treatments.

For the past two decades, Alzheimer鈥檚 research has been dominated by the 鈥渁myloid cascade hypothesis鈥�: the idea that it is the plaques themselves that lead to the cognitive problems of Alzheimer鈥檚. They are aggregations of a protein called amyloid beta, which forms naturally in the brain, but whose production somehow goes into overdrive during Alzheimer鈥檚 disease (see 鈥淏rain defence gone wrong?鈥�). The proteins clump together to form plaques, which are toxic to neurons, eventually killing them, or so the theory goes ().

Drug developers immediately grasped the implication of the theory, that medicines able to block or break up the plaques should slow, or even reverse, the progression of the disease. This idea has guided millions of dollars鈥� worth of drug development effort. Just about every potential Alzheimer鈥檚 drug in the pipeline targets amyloid and its supposed toxicity.

The excitement has faded fast. So far, at least, none of the treatments derived from the amyloid hypothesis has ever resulted in significant clinical improvement in clinical trials. 鈥淚t has been a problem for people working on [the amyloid plaque theory] for 20 years 鈥� the drugs that have come out of it have all failed at stage II or III of clinical trials,鈥� says Susanne Sorensen, head of research at the UK鈥檚 Alzheimer鈥檚 Society. Sorensen has never seen a trial that reported people getting better.

鈥淭he drugs coming out of the amyloid plaque theory have all failed late-stage clinical trials鈥�

Take b-mab, for example. This drug was developed to clear amyloid plaques from the brain, but results released in 2008 showed that it had no significant effect on the rate of cognitive decline (). That raised a question. Was b-mab failing to clear the plaques, or were the plaques themselves not the problem?

We are now beginning to get answers. A team at the University of Pittsburgh, Pennsylvania, led by William Klunk and Chester Mathis has developed a brain-imaging marker called PiB that selectively sticks to amyloid plaques, lighting them up in PET scans. The marker means plaques can be seen in living people, and changes in plaque size can be monitored.

In February, a Finnish team used PiB to show that when people with mild to moderate Alzheimer鈥檚 were given b-mab, the plaques did indeed clear 鈥� by as much as 25 per cent over 18 months compared with a placebo (). Yet people given b-mab experienced the same progression of symptoms as those on the placebo. In other words, the drug was doing what it was supposed to do, but without slowing the disease.

The study seems to confirm what has long been suspected from post-mortem evidence: that plaque size and dementia symptoms don鈥檛 correlate. That has always been the central objection to the plaque hypothesis, says Dominic Walsh, a neurologist at University College Dublin in Ireland. 鈥淟ots of people have Alzheimer鈥檚 plaques but are not demented.鈥�

鈥淟ots of people have Alzheimer鈥檚 plaques but are not demented鈥�

If the plaques aren鈥檛 responsible, then what is? Alzheimer saw more than plaques in Deter鈥檚 brain: there were also the tangles, which form inside neurons themselves.

The tangled material is now known to be made of a protein called tau, which can build up until it almost fills the neuron, which then dies. Crucially, unlike with plaques, the number of tangles in a patient鈥檚 brain seems to correlate well with their level of dementia.

Recent studies also suggest that stopping tau molecules from clumping together could be an effective drug target. A drug called Rember, made by a Singapore-based start-up called TauRx Pharmaceuticals, has shown promising results in early trials, and the company claims to have an even more effective version that will begin final-stage trials this year.

That might seem to be the end of the amyloid theory. Not quite. A number of studies have investigated what triggers tau to accumulate in neurons in the first place, and they point right back to amyloid beta (). So even if tau is the direct cause of dementia, amyloid beta build-up could still be the trigger.

If that is the case, then why don鈥檛 plaque-targeting drugs seem to work? A growing number of researchers suspect that the problem is that they have been looking at the wrong form of the protein. There is increasing evidence that short chains of amyloid beta molecules known as oligomers are really responsible for the symptoms of Alzheimer鈥檚 disease. Oligomers 鈥� small, soluble precursors to the large, insoluble plaques 鈥� appear from cell and animal studies to be damaging to neurons. In fact, many now believe that the plaques may actually be the brain鈥檚 way of disposing of something toxic.

In April, this theory got a huge boost from a study by Sam Gandy at Mount Sinai School of Medicine, New York, and his colleagues. The team engineered mice to produce oligomers but stop short of developing plaques and found that the animals experienced the same memory and cognitive problems as those that had plaques did (). 鈥淎t least in mice, the oligomer dose did seem to correspond pretty much with the severity of the memory problems,鈥� says Gandy.

The real bad boys

The study is a coup de gr芒ce, says Rudolph Tanzi, an Alzheimer鈥檚 researcher at Harvard Medical School and Massachusetts General Hospital in Boston. 鈥淚t finally shows exactly what all the previous data were pointing to but never directly showed 鈥� we can have a brain with no plaques but still have problems.鈥�

Gandy thinks the oligomers may kill brain cells by making them leaky. Like cell membranes, amyloid beta is relatively hydrophobic, which could draw the two together. If the oligomer then punctured the membrane, it would kill the cell. Alternatively, the oligomers may be acting indirectly: other studies have shown that they can cause the precursors of tau tangles to appear (). No one knows for sure, though, and to find out researchers first need to know exactly which size of oligomer is the guilty party.

Tanzi suggests dimers 鈥� pairs of amyloid molecules linked by strong covalent bonds. 鈥淲e believe that these are the real bad boys.鈥� His team has shown that people with Alzheimer鈥檚 have equal numbers of antibodies to the amyloid monomer as those without the condition, suggesting that both groups鈥� immune systems are able to mop up any excess of the amyloid monomer that might accumulate as we age. However, the Alzheimer鈥檚 group had significantly fewer antibodies against the stable dimers, so would be less able to remove this seemingly toxic form of amyloid beta ().

Whether or not the dimers are the true culprits, or whether larger forms of soluble amyloid beta such as the 12-chained dodecamer are responsible, the oligomer theory is gaining popularity in the field. The theory sounds convincing, says Sorensen.

Dennis Selkoe, a neurologist at Harvard Medical School involved in formulating the original amyloid cascade hypothesis, thinks it鈥檚 too early to rule out plaques completely, because they don鈥檛 permanently sequester oligomers. Over time, they can also release them. 鈥淚 believe there鈥檚 a limit as to how many oligomers can be efficiently stored within plaques, and when these limits are exceeded, patients begin to experience more and more synaptic dysfunction from free-floating oligomers.鈥�

鈥淲hen plaque limits are exceeded, people begin to experience more and more synaptic dysfunction鈥�

Other researchers are still to be persuaded by the idea. 鈥淭he major flaw in the oligomer idea is that nobody has really seen these things in either living patients or autopsy brains,鈥� says Mark Smith, a neurochemist at Case Western Reserve University in Cleveland, Ohio. They can only be seen after you have isolated them, he points out, so they could just be artefacts of the isolation procedure.

For Gandy, finding a PiB-like marker to show up oligomers in vivo is a priority. Developing PiB took close to a decade, so it might take a while. There might be other ways, though. Not all of the Alzheimer鈥檚 drugs being tested at the moment are designed to break up amyloid plaques. Some are targeted much earlier in the process, stopping amyloid beta formation at source 鈥� so they should stop oligomer formation too.

One group of drugs, called gamma secretase inhibitors, stop amyloid beta formation by blocking the enzyme that makes it. Although one such drug recently failed a clinical trial, another, developed by drug firms Eli Lilly and Elan Pharmaceuticals, is currently in final-stage clinical trials.

Another promising drug prevents amyloid beta from forming oligomers, as well as breaking up plaques. PBT2 has shown cognitive benefits in trials, according to researchers at Prana, an Australian biotech company. They presented their results at the American Aging Association meeting in Portland, Oregon, in June, adding that the drug also frees the zinc and copper trapped in plaques that are needed for the functioning of nerve cells.

Selkoe suspects that for any of these drugs to work, catching the disease early will be key, which could explain why so many have been disappointing. Clinical trials target people with mild to moderate Alzheimer鈥檚, and Selkoe argues that attempting to treat the disease when it is already at the moderate stage is too late. Ideally, drugs should be given before symptoms appear, he says. PiB could be very useful here, as the marker might allow pre-symptomatic cases to be identified.

Whichever theory is correct, that Alzheimer鈥檚 research is branching out can only be a good thing. 鈥淏efore, it was heresy to question the amyloid hypothesis,鈥� says Smith. 鈥淚 think people are getting a little braver.鈥�