Perched on the edge of the San Francisco Bay, flanked by the brown sun-scorched slopes of San Bruno Park and Sweeney Ridge, Athena was the slick new contender that everyone thought would outsmart Alzheimer’s. It had some of the brightest minds in the field–including Dora Games, inventor of the Alzheimer’s mouse that provided support for John Hardy’s amyloid hypothesis. With the amyloid hypothesis as its foundation, the company made a list of all the therapies it wanted to test in the mice.
Schenk’s idea was low on that list. ‘Nobody wanted to do it,’ he said, laughing. ‘We had a list of thirty-three therapies we wanted to try on the mice and it was listed as number thirty-two. I couldn’t even get any animals to do the experiment.’ One of his colleagues thought the idea was so absurd that he put it on a list of bad ideas, which he stuck in the lab for all to see. As further ridicule, he gave Schenk the ‘broken clock’ award–even a broken clock is right twice a day–to which Schenk would retort, ‘Well, at least it’s exactly right twice a day.’
But with patience and dogged persistence, Schenk’s time finally came. Managing to obtain a group of mice left over from somebody else’s work, he performed the immunisation, sacrificed the mice, and sent their brains off for analysis. Then he waited. And waited–his gamble was hardly considered urgent–until, months later, he got a phone call from Dora Games herself. ‘You’re not going to believe this,’ she said. ‘But we’re—’
‘Not seeing any plaques in the mice that are vaccinated, right?’
So how did it work? I’ve spent years culturing microglia and can honestly tell you that we really don’t know. The more we learn about microglia, the more complex their character turns out to be. Nonetheless, microglia tactics are basically twofold. They can secrete chemicals that kill parasites by degrading the parasite’s DNA, or physically engulf the intruder in a process called phagocytosis (Greek, ‘to devour’). Of course, Athena’s neuroscientists didn’t care how the patient’s microglia chose to eviscerate the plaques, so long as they did it safely and stopped Alzheimer’s as a result.
This now started to feel like an achievable feat. Between 1997 and 2000 vaccinations in rabbits, guinea pigs and monkeys all supported Schenk’s discovery.6 The vaccination even appeared to improve animal cognition. With that, the pharmaceutical companies Élan and Wyeth began human trials.
Human trials, also known as clinical trials, are typically split into four phases. Phases one and two are all about safety. In phase one the drug is given to a small group of twenty to eighty people to determine a safe range of doses. If no adverse effects are spotted the drug advances to phase two, where hundreds of people are treated and tests are performed to see if it has any biological effect. Most drugs, unfortunately, do not make it past phase two.7 For those that do, phases three and four represent the peak of the mountain. In phase three thousands of people are tested over the course of several years; side effects are monitored; and if the drug appears to have worked it’s then marketed and approved by agencies such as the FDA or EMA (European Medicines Agency). Phase four is a kind of follow-up to see how the drug is faring in the general population, and if there are any long-term effects that weren’t detected earlier.
In a small phase one clinical trial of just twenty-four patients, a single dose of Schenk’s vaccine appeared to be safe. Multiple doses were then given to more than seventy patients. Again, no adverse effects. Confident it was safe and worth pursuing, Élan and Wyeth moved to phase two, where 300 patients received the vaccine.
Scientists the world over were on tenterhooks. This was the first real-world test of the amyloid cascade hypothesis.
It was a disaster. Seventeen patients developed a dangerous form of brain inflammation called encephalitis, causing confusion, fever, and, if left untreated, seizures, stroke and death. In January 2002 AN-1792 testing was immediately aborted. After all the early promise it was a severe blow. And a hard lesson.
Schenk was stunned. ‘Because we didn’t see anything in the animals…’ he lamented to me in a quiet, solemn tone, ‘but it may have come and gone without us being able to detect it.’ Determined the tragedy wouldn’t be in vain, scientists around the world began an extensive follow-up of every patient from the trial. The findings were a mixture of encouraging, disappointing and just plain weird: encouraging because the first post-mortem showed a brain almost entirely clear of plaques; disappointing because Sid Gilman–Élan’s elected expert to chair the trial’s safety-monitoring committee–reported that of the 300 patients only 59 actually mounted an immune response; and plain weird because some patients did show a flicker of improved memory, even though a subsequent MRI scan showed that their brains had actually shrunk. How could a shrinking brain be found alongside increased cognition? ‘We still don’t know,’ said Schenk. ‘We may never know.’ Only one thing was unanimously agreed: to watch every vaccinated patient like a hawk.
Four years later it was revealed that 159 patients did eventually show some improvements in cognition. Schenk’s idea was alive again, and so if scientists could overcome the side effects then the makings of an effective treatment were in sight. Fortunately someone had already stumbled across a possible solution. Shortly after the trial ended, a Swiss psychiatrist named Christopher Hock found that patients who had made antibodies to beta-amyloid did better on tests of language, attention, memory and self-care than those whose immune system had not made antibodies.8 Switching tactics, Schenk devised an antibody-based vaccine: Bapineuzumab, or ‘Bapi’, was an antibody made in mice but artificially tweaked for humans. The genius of this strategy was that patients would not have to mount a full-blown immune response because the antibodies to the plaques would already be present. It was less aggressive, and thereby reduced the risk of encephalitis.
In 2006 clinical trials were under way and the only side effect was a little water in the brain–cerebral oedema, quickly remedied by lowering the dose. By December 2007 the drug made it to phase three and more than 2,000 patients spanning North America and Europe, aged fifty to eighty-five, were enrolled.
It was the largest, most audacious attempt to combat dementia. Alois Alzheimer could only describe what he saw, William Summers could only delay the symptoms of the disease, but now Dale Schenk might be able to prevent the disease from taking hold. As the trial got under way, US pharmaceutical giants Pfizer and Johnson & Johnson stepped in, investing hundreds of millions of dollars in Bapi–the silver bullet to end an epidemic.
But it too failed. In August 2012 the results were in and Bapi showed no therapeutic benefit in all phase three trials, its effect on memory no better than a placebo. With the financial cost of the failure staggeringly high, Johnson & Johnson and Pfizer swiftly halted development.
There was widespread doubt over the amyloid hypothesis. Even early, highly influential supporters like Zaven Khachaturian–director of the NIA and recruiter of amyloid mastermind George Glenner–began to express reservations. ‘The amyloid hypothesis became such a strong scientific orthodoxy that it began to be accepted on the basis of faith rather than evidence,’9 he told one reporter, adding, ‘no one has stepped back to ask whether our basic premise about the disease is the correct one.’
Schenk had his own doubts, but there were three gaping holes in the trial’s design. First, how did we know these patients really had Alzheimer’s? Post-mortem was still the only way to know definitively; perhaps they had another kind of dementia. Second, there was still no way of rigorously separating early from mid-stage cases; perhaps that skewed the overall result. And third, John Hardy and many other Baptists all agreed that the dose was too low; risks aside, there could be no kid gloves in this fight.
‘We couldn’t figure out who had the disease. We couldn’t separate mild from moderate. And we were limited to low doses,’ said Schenk. Another drawback, he explained, was the trial’s benchmark for success. Because the activities of daily living vary so much between people–some people might do crosswords all the time, for instance, while others read or
sew instead–the FDA demanded that trial candidates score highly on two different sets of cognitive tests, instead of the usual one. This set the bar for a positive result very high. ‘So the sad part is that this drug probably would’ve worked for some people.’
Schenk’s criticisms were soon backed up when scientists re-examined the drug using a powerful new technology. Pioneered at the University of Pittsburgh, Pennsylvania, ‘PiB’ (or Pittsburgh compound B) was a radioactive dye that bound to beta-amyloid in living subjects. Combined with conventional brain scans, PiB could actually show the spread of amyloid in the brain.10 It was also a strong diagnostic tool: APOE4 carriers were more likely to show a bright PiB signal, as were carriers of APP mutations. But to the amazement of those involved in the Bapi trials, 30 per cent of the recipients were PiB-negative. They didn’t have Alzheimer’s. They had been misdiagnosed.
And so the flaws of the trials, along with the ambiguous nature of the results, gave researchers enough reason to continue pursuing vaccine therapy. They’re still working on it today.
It was at this point that I had to ask: what did Schenk think caused Alzheimer’s? He paused and breathed a heavy sigh. ‘I don’t think there’s a single cause. I think it’s like heart disease, and having plaques and tangles is like saying you have clogged arteries. You can have clogged arteries without having heart disease. And even though everybody views me as a Baptist, it’s just that amyloid’s been the most treatable drug target. That’s why we’ve all focused on it.’
I told him about my conversations with John Hardy and Allen Roses, and how Roses had seemed disgruntled that people weren’t paying enough attention to his APOE4 discovery. Schenk gave me a knowing smile. ‘Well, John Hardy’s a geneticist. Allen Roses is a philosopher. If he’s disgruntled it’s probably because he feels it’s a target that we’ve missed, and he’s probably right. But I swear to God we all tried our hardest to figure it out. Everybody had an APOE4 programme. We had one for eight years. Nothing came of it. That doesn’t mean that APOE4 and the tangles are bad targets. It’s just been harder to make a drug for them.’
Given all that, what will the cure look like? I asked. ‘To be honest, I like to talk about conquering Alzheimer’s rather than curing it. Because it’s like asking, how do you cure heart failure? Well, you get a new heart. You can’t get a new brain. So I think there’s going to be a way to prevent it, or push it off many years. That’s how we’ll conquer it.’
I wasn’t sure how I felt about his answer. Like many families and patients, I can’t help but hope for something that reverses the symptoms altogether, rather than just holding back the disease–something that reaches beyond the gloomy sea of dead neurons and pulls a memory back into the light. This might not be a fantasy (as we shall see in chapters fourteen and fifteen), but it’s certainly further away.
One might wonder at the significance of these drug trials. With failures in the past the vaccine therapies have a lot to prove. I am yet to be convinced that a vaccine will work for everyone; Alzheimer’s seems too nuanced for that. But if there’s anything to provide real hope, it’s a scientific lesson best articulated by a woman who was neither a scientist nor a physician. Gertrude Stein said: ‘A real failure does not need an excuse. It is an end in itself.’11
We have known for a long time that the pantheon of science is decorated with failure. Failures are the moving force in science: they seal off one possibility in order to expose another; they force us to look at the problem in a new light. We owe a huge debt, therefore, to the researchers whose life’s work leads to a cul-de-sac. They are indirectly showing us the correct path.
Altogether, these so-called ‘prevention trials’ promised a sea change in the fight against Alzheimer’s. But while the concept of Alzheimer’s as a process got scientists thinking about early prevention, this, they realised, depended critically and inexorably on something else: early detection.
8
Swedish Brain Power
Before we go any further, I just want to make it clear that I don’t want you to tell me that I’ve got Alzheimer’s.
Anonymous patient’s request to physician, British Medical Journal, March 2014
THE MÖLNDAL HOSPITAL in Gothenburg, on the west coast of Sweden, inhabits a complex of tall red-brick buildings overlooking a wide expanse of countryside and wooden houses. A highway cuts through this landscape, where a few taxis huddle on a cramped collection point. Apart from the modern, sky-blue trams gliding commuters to and from the city, it’s a decidedly unremarkable place.
But within these ordinary walls, an intense and momentous search is happening. The process uses drops of liquid so small, that state-of-the-art robotics have been built specifically for the task. They’re looking for something Alzheimer’s researchers have spent the past two decades searching for: biomarkers–biological clues observable long before symptoms appear, such as chemicals found in blood and other bodily fluids. Anything, in other words, silently lurking under the skin presaging a dark neurological future. After the failure of Big Pharma’s antibody trials, identifying biomarkers for early intervention became the field’s new priority.
The idea was far from new. In the mid-1990s scientists noticed that beta-amyloid and tau also appear in spinal fluid, the colourless liquid enveloping the brain and spinal cord, providing protective buoyancy as well as a good filtration system.1 And, unsurprisingly, the levels differed between healthy people and those with Alzheimer’s: beta-amyloid is reduced in the spinal fluid of Alzheimer’s patients while tau is increased. Why they behave this way in spinal fluid isn’t entirely clear, but we think it’s because beta-amyloid becomes trapped in plaques inside the brain, while tau oozes out of the brain as neurons slowly fall apart. It has been found that this can actually happen twenty to thirty years before symptom onset. By the late 2000s, studies even showed that such observations could predict Alzheimer’s with 90 per cent accuracy. A new ‘pre-clinical’ phase of Alzheimer’s was coined in 2011, and scientists scrambled to find biomarkers wherever they could.
On a Monday afternoon in December 2015 I walked into the Mölndal Hospital and was greeted by a convivial man with a blond ponytail and a profusion of infectious energy named Henrik Zetterberg. In the wake of everything I’d learned about the expanding graveyard of drug tests, I’d travelled to Sweden hoping to glimpse a brighter, smarter future for clinical trials.
Growing up in the rural suburbs of west Gothenburg, near the stony reefs of the Kattegat Bay, Zetterberg spent his school holidays working in local nursing homes for extra pocket money. There, he saw first-hand the devastating effects of Alzheimer’s, long before his classmates had even heard its name. His parents were not particularly academic, but when they spotted the young Swede’s predilection for science, they encouraged him. His father started switching the radio on to listen to programmes by the Swedish molecular biologist Georg Klein, and Zetterberg became entranced by the intense, beguiling way he described a scientific conundrum. He went on to study medicine and, when it was time to specialise, probing the organs most accessible to physicians wasn’t sufficiently Kleinesque for Zetterberg; he wanted to probe something that didn’t surrender its secrets so readily. He specialised in clinical neurochemistry, and like an oceanographer studying the lakes and rivulets of the earth, Zetterberg set out to explore the hydrology and marine life of the nervous system.
Taking a seat in his office, I cut straight to the chase by asking how infallible these spinal fluid signals really were.
‘We’ve been able to show that almost all people with biomarkers for plaques and tangles eventually develop Alzheimer’s,’ he told me in an astonished, surreptitious whisper. ‘It’s been one of the biggest, most important results in recent years.’
I was awestruck. In the future perhaps everyone would want to be tested. Perhaps the entire world would face the same choice as Carol and John Jennings.
With such a long time lag between disease initiation and mental collapse, Zetterberg thinks of Alzheim
er’s not as a thief in the night but rather a Shawshank Redemption-style escape artist. He thinks plaques and tangles are initially seeded in the brain during middle age–and then, like Andy Dufresne in his prison cell, they quietly start burrowing their way out. ‘I think you start to get small seeds in your brain when you’re forty or fifty–it’s probably happening to me right now!–and that build-up lasts for decades. But it’s not toxic, and beta-amyloid is basically sealed within plaques. But then something happens, and for about five to ten years you get new sub-seeds spreading. Then tangles form, the symptoms finally come, and the brain and hippocampus start to shrink.’
Zetterberg is certainly not shy of thinking outside the box. To see just how indicative of brain damage fluid signals are, he recruited the help of ice hockey players from the Swedish Hockey League.2 This national obsession constitutes 288 professional athletes spread over twelve teams, and each player is only too aware of the risk of concussion and/or traumatic brain injury. ‘It’s really troubling them, because the sport is not about knocking someone out; it’s about scoring, and these players have seen their teammates severely concussed.’
During the 2012–13 season, thirty-five players suffered concussions; some were so bad they knocked the player unconscious. Just before the season began, Zetterberg took blood samples from the players of two teams. He then repeated this on players at various time points after injury and found that tau–the main ingredient of tangles–rose in the blood within one hour following a concussion. He could use the levels to predict how many days it would take for the player to be well enough to return to play: the higher the level of tau, the longer it took for the player to recover.
Although the relationship between sports-related impacts and Alzheimer’s is still debated, it’s well established that boxing and American football can lead to other neurodegenerative disorders, such as Parkinson’s and a dementing syndrome called chronic traumatic encephalopathy, respectively. These hard-hitting sports often cause the head to rotate rapidly–which, for nerve cell axons, creates a kind of shear, twisting physical force: the kind that bridges must contend with during high winds. It’s a serious problem, and today Zetterberg is working with England’s Saracens Rugby Club to develop impact sensors that detect these forces and instantly alert the player to take a break. Even for those of us who don’t play these sports, his message is to avoid head injuries at any cost. The repercussions last longer than we think.
In Pursuit of Memory Page 10