Half a million people in the UK are living with Alzheimer’s disease, the most common form of dementia. And while the risks generally increase with age, thousands are afflicted under the age of 65. Inheritable genetic conditions can lead to familial Alzheimer’s, which can afflict people as young as 30. There is no known cure. Some medications can reduce memory loss and aid concentration, but these merely alleviate the symptoms or boost the performance of those neurons in the brain that remain unaffected. They do nothing to stop or slow down the killing-off of brain cells by this neurodegenerative condition. It is a bleak picture. Part of the problem with developing drugs is that the causes of Alzheimer’s are still not fully understood. Moreover, the disease is also challenging to combat because, like cancer, it is not caused by an invading pathogen. It arises from our own biology – from something that our cells are prone to doing. But, also like cancer, one of the most promising current approaches to a cure enlists our body’s own defences, using the immune system to ward off the disease by means of immunotherapy. Immunotherapy works in the same way as vaccines, by helping the immune system recognise and attack cancer cells, and many researchers and some pharmaceutical companies are now striving to make a vaccine against Alzheimer’s. Some immunotherapeutic drugs are now in clinical trials, being tested on human volunteers to see if they are safe and effective. There is good reason to hope that the vaccination strategy might ultimately be effective for treating or warding off this widespread, devastating and fatal condition.
Alzheimer’s is caused by two rogue proteins – the molecules that carry out much of the work in our cells. Proteins are chain-like molecules encoded by genes, which typically fold into compact blobs to function properly as enzymes. One of them, called amyloid beta, can misfold into a “sticky” form that then clumps together into aggregates – called plaques – in the brain. These can accumulate outside neurons, and are toxic to them. The risk of misfolding increases with a person’s age, but it can also happen early in life for people with a particular mutation in a gene called APP, which stands for “amyloid precursor protein,” the protein that becomes amyloid beta. People who inherit one of these APP mutations “will get Alzheimer’s, typically in their 40s or 50s with a near 100% certainty,” says Nick Fox, a neurologist at University College London. But siblings who don’t inherit the mutation will have no more chance of getting Alzheimer’s than anyone else. That makes it look as though amyloid beta is the primary culprit of Alzheimer’s. But there’s another protein involved too, called tau (rhymes with “wow”). Whereas no one is quite sure what the natural role of “healthy” amyloid beta is, tau is known to maintain protein filaments called microtubules inside nerve cells, which Fox calls “the railway tracks of the neurons’ transport system.” If tau folds into an abnormal shape and doesn’t work properly, the tracks break up and form tangles inside the neurons, which again stops them working and leads to their death. What’s worse, an abnormally folded tau protein may be able to spread the misfolding tendency to other neurons, in a kind of contagion.
The consequences of aberrant amyloid beta and tau – formation of plaques and tangles in brain tissue – were seen by the German psychiatrist Alois Alzheimer himself when he identified and studied this form of neurodegeneration in the 1900s. But it’s still not agreed which is the more important, and the field has been dogged by arguments between the so-called “baptists” (who believe amyloid beta protein, BAP, is the prime cause) and “tauists” (who blame tau). Some say that amyloid beta sets up the danger but tau sets it off: amyloid plaques build up around neurons in the brains of healthy people, but that’s only a problem if tangles caused by tau are present too. In this view, amyloid is the match, and tau the fire. At any rate, without amyloid there seems to be no danger – no fire without matches – so anti-Alzheimer’s drugs are being developed to clear it. It’s not obvious how best to do that, though. It is said that when one of the pioneers of Alzheimer’s immunotherapy, the late Dale Schenk of Elan Pharmaceuticals in San Francisco, convened a lab meeting in the 1990s to discuss strategies for developing drug treatments, lab members listed all the possible approaches on a whiteboard – and the idea of a vaccine was considered the worst. Alzheimer’s was regarded purely as a result of age-related wear and tear; no one thought it had anything to do with the immune system. But Schenk (who died of pancreatic cancer in 2016 at the age of 59) tried it anyway, and the results astonished the research community. He and his colleagues studied mice with a gene mutation that conferred a condition similar to Alzheimer’s by producing a faulty amyloid protein. The mice were vaccinated with fragments of that protein to induce an immune response. Their bodies produced antibodies that would attack amyloid as it built up plaques. Surprisingly, the antibodies seemed able to get from the bloodstream into the brain, something that is normally blocked by membranes that form a “blood-brain barrier”. This work led to the development of a human vaccine called AN-1792, which Elan put into clinical trials.
It looked promising at first. James Nicoll of the University of Southampton was in one of the teams that looked at the results; in 2003, when one of the patients in the trial died of unrelated causes, his group had a chance to examine the person’s brain post-mortem. “We found evidence of quite extensive removal of amyloid plaque,” he says. “It showed that the approach does work.” Fox became drawn into the quest because of his expertise in brain-imaging using the technique of MRI, which supplies a means of both tracking the course of Alzheimer’s and assessing treatments while patients are still alive. Because of neuron death, the brain can shrink by as much as 20% for people with the condition. So MRI offers a quick way to track how much effect a drug is having. But in the AN-1792 tests, says Fox, imaging scans showed areas of brain swelling due to inflammation. At the phase II stage of clinical trials, which involves a relatively large patient group, about 6% of those given the treatment suffered inflammation. Their immune system seemed to be over-reacting, just as it does in an allergic response. The inflamed brain caused symptoms similar to meningitis. Most patients recovered fully, but the trial was stopped. “The whole field was rocked,” says Fox. “It was such a setback if you couldn’t control the immune response safely.” Still, the idea wasn’t abandoned. Perhaps, instead of relying on the body to make its own antibodies – and risk an over-reaction– you could make antibodies against amyloid outside the body and inject just the amount needed? They needn’t even be human antibodies; with a little modification, they could be raised in other animals, such as horses. That approach has led to a number of candidate antibody drugs able to provoke immune attack safely on amyloid plaques. But clinical trials have so far produced no sign of improvement in cognitive function. “Perhaps the treatments were too little or too late,” says Fox. Given the earlier experience of inflammation, the doses might have been too cautious. Trials are ongoing, however.
One antibody drug called aducanumab, currently being tested by the company Biogen, has shown some promise in higher doses, with possible cognitive benefit as well as safe clearance of amyloid. Large-scale trials will be completed in about a year’s time. Unfortunately, this type of treatment, known as “passive” immunisation, would be hugely difficult and costly to administer because it requires patients to have regular intravenous infusions of the drug. It’s not clear how a health service could cope with that for everyone who shows signs of Alzheimer’s, or is merely thought vulnerable to it. “Passive immunisation is hugely expensive,” says Nicoll. “It’s difficult to envisage how you could treat many people over many years with regular infusions.” So he sees this approach more as a demonstration of the principle that antibodies can do the job. That is why vaccination – an “active,” once-only treatment that stimulates the body’s own immune system – still looks more attractive. The problem of inflammatory side-effects remains a concern but at least it’s becoming better understood. Nicoll believes that when amyloid is broken down by the antibodies, the fragments dissolve in the blood and end up in the walls of blood vessels, which become damaged and leaky as a result, causing “microbleeds” in the brain. If amyloid plaque formation can be prevented , that problem shouldn’t arise. Hopes were rekindled recently by the results of another candidate drug in clinical trials, called UB-311 and produced by Dublin-based United Neuroscience. The drug is an artificial protein-like molecule that mimics amyloid and provokes a natural immune response. Apparently, UB-311 doesn’t have serious side-effects – the tests so far show that it “is definitely safe”, according to Mei Mei Hu, the company’s chief executive officer.
The key question, still unanswered, is whether any of these treatments can stop or even reverse the decline in brain function caused by Alzheimer’s. Once neurons in the brain have been killed, the brain can’t replace them. “The large-scale studies [of drugs] have been disappointing in terms of preventing cognitive decline,” says Nicoll. Amyloid is not the only target. Vaccines against tau protein are also being studied – one of them, called AADvac-1, developed by Axon Neuroscience in Slovakia, is in phase II clinical trials now and the results are due next year. But an Alzheimer’s vaccine would pose difficult choices. Would it be administered to prevent the disease developing at all, much as the measles vaccine is given to children today? Or should it be a “secondary” treatment, given only when there is some sign of plaque build-up? “The logical thing with vaccination is to go very early,” says Fox. One concern is that the drug trials so far have intervened too late in the process to have much effect: amyloid aggregation can appear up to 15 years before a person shows any neurodegenerative symptoms. It’s often said that “we’ve been treating the last 10 years of the disease as if they were the first 10 years,” Fox says. On the other hand, vaccination of healthy people is often controversial, not least because of the risk of side-effects or over-responses, even in just a few individual cases, in people who would never develop the disease.
“It’s frustrating that we still don’t know after 20 years if immunisation is going to be a useful approach for Alzheimer’s or not,” says Nicoll. But he sees some cause for optimism in the existing evidence from animal studies that antibodies against amyloid protein can prevent plaques from forming. He says there are currently two studies being conducted that deliver plaque-busting drugs to people with a genetic susceptibility to early Alzheimer’s, to see if the disease can be prevented before it occurs. Some of the participants in these trials carry the APP mutation that would make neurodegeneration otherwise inevitable in mid-life. If that is avoided, it should be a clear indication that immunisation can work. “Hopefully, we’ll get answers in the next few years,” says Nicoll. In the absence of any known cure, people living with Alzheimer’s are typically eager to give these trials a shot, says Fox. The people he works with “are repeatedly disappointed [with failures of candidate treatments], but rarely resentful. They are realistic, and really appreciate the efforts being made.” If we’re lucky, the best line of defence against this form of dementia will turn out to be the body itself.
Gum disease link to Alzheimer’s risk
A possible link between gum disease and Alzheimer’s is prompting some people to pay more attention to dental hygiene. That’s no bad thing: gum disease isn’t just bad for your teeth but offers an entry point for all kinds of pathogenic bacteria. Whether flossing will do anything to lessen your risk of dementia, however, remains to be seen. The claim, made by researchers at the biotech start-up Cortexyme in South San Francisco and others, is that the bacteria Porphyromonas gingivalis, which cause gum disease, were found in the brains of people who had died from Alzheimer’s alongside gingipains, the toxic proteins the bacteria produce. The bacteria were also detected in people with only very early biological indicators of Alzheimer’s, suggesting that the gum disease wasn’t simply caused by cognitive decline. It is thought gingipains disrupt the tau protein. They reported that infecting mice with the bacteria could trigger an Alzheimer’s-like condition, and that drugs that block the effects of gingipains could protect the mouse neurons. The results might lend some support to an unorthodox theory, championed by Harvard neurologist Robert Moir, that amyloid is a defence against pathogenic microbes. Even Moir, however, hesitates to conclude from the new study that P. gingivalis is itself a cause of Alzheimer’s. There are echoes here of the early days of cancer research, when it too seemed to be a shared endpoint of several possible causes, including infections. These are important clues, but it’s not yet very clear what they are telling us.
Credit: Philip Ball for The Observer, 3 March 2019.