In Pursuit of Memory

by Joseph Jebelli

  I wasn’t alone in that wish. Cramer’s findings drew instant attention from the press. Landreth received a torrent of correspondence from reporters and, more importantly, the relatives of Alzheimer’s patients themselves. ‘We published in February,’ he stated, ‘and I was not able to answer my phone until November. I got hundreds of calls and emails from all these desperate people. My secretary was in tears listening to their stories. It was heartbreaking.’

  ‘People want something,’ Cramer elaborated. ‘They need something.’ Despite warnings about using the drug off-label, some people went ahead anyway, more than willing to take matters into their own hands. In the press the story of one Mandy Vear, from Rossendale, England, began to surface.6 As Vear’s father’s condition was descending into outright violence against his family, she pleaded with her doctor to write him a prescription for bexarotene. But the physician refused, for bexarotene’s side effects cast a dark shadow by raising triglycerides: blood fats linked to diabetes and heart disease.

  Another story featured an anonymous Belgian patient whose physician agreed. Sixty-eight years old, the man reportedly took the drug every day for twenty-three months and was monitored by a team at the Université catholique de Louvain, in Brussels, Belgium.7 Tantalisingly, his memory somewhat improved and he scored higher in several tests of cognition. The problem, as one would expect, is that there was no way to rule out a placebo effect. And so this anecdotal case fossilised as just that: anecdotal, informal, unreliable. ‘You’ve just got to take it for what it’s worth,’ Landreth made clear to me. ‘It supports the idea, but you certainly wouldn’t base any subsequent action on a case report.’

  But where were the human trials? I wondered.

  I learned that four other groups, inspired by Cramer’s discovery, had already set about replicating her data. Before any discovery is given credit, before it can launch human trials, it faces the gauntlet of widespread replication and doubt. This isn’t pretty; scientists can shoot down someone’s work with the accuracy of an Olympic archer. Which, unfortunately, is exactly what they did. Just as Cramer and Landreth were pushing for clinical trials, all four groups announced that they categorically could not reproduce Cramer’s data. Had she made a mistake? Could her discovery be an illusion, a quirk of her batch of mice, perhaps? Was this all just a tempest in a teapot?

  In May 2013 Nature published a disheartening article outlining the dissenters’ views.8 Their chief criticism was that bexarotene didn’t actually affect Alzheimer’s plaques. Rather, the drug diminished levels of a smaller, free-floating form of beta-amyloid called oligomeric amyloid: a kind of intermediate brand of the toxin, which clusters together long before plaques appear. Yet many believed this type of amyloid was more central to the disease process. A stack of scientific literature had shown that oligomeric amyloid could scramble synaptic communication like hail bombarding a television antenna. And while plaques certainly looked more deadly, their invisible predecessors correlated better with memory impairment and cognitive decline. Some even claimed that clinical trials had failed because they’d tried to remove plaques, when they should really have tried to remove oligomers.

  For Landreth, it was all a lot of hot air. ‘It pissed me off that this entire discussion centred on plaques, when we explicitly showed that plaques don’t matter! All the plaques say is “things have gone badly in the brain”. But if improved memory and cognition is the ultimate goal, why should plaques matter? It’s clear that these small oligomeric species affect synapses, and I think we improved the animals’ behaviour by removing them from the brain.’

  He was also quick to point out that other groups had prepared the drug differently. They’d dissolved its raw powder in an artificial liquid, instead of simply using the pill form, as Cramer had. The reason that matters, Landreth maintained, is that the former stays in the blood for minutes while the latter remains in circulation for hours. And in the realm of molecular genetics, that disparity was titanic.

  Although Landreth’s rejoinder wasn’t enough for Big Pharma to weigh in, others weren’t ready to see the lead so easily dispatched. A group of private donors–all anonymous Alzheimer’s relatives–raised over $1 million to fund a small clinical trial, led by Jeffrey Cummings at the Lou Ruvo Center for Brain Health in Las Vegas, Nevada. Completed in August 2014, twenty people over a period of four weeks received either bexarotene or a placebo. Remarkably, the drug did appear to reduce amyloid, but only in the people who didn’t have the APOE4 genotype. As Cummings scrutinised the data further, he reached two conclusions for that: ‘It could be that it only works in APOE4 negative individuals,’ he explained over the phone. ‘Or, I think equally as likely, we may simply need to expose these people [to bexarotene] for longer, because the amyloid in APOE4 carriers is denser and more aggregated.’

  Cummings is currently planning a second, year-long trial of bexarotene. Even if the drug fails to ameliorate the symptoms of dementia, it may plant the seeds for one that does. And a clever chemist, he argues, could theoretically remove the molecular components causing the potential side effects. Confident, innovative and reasonable, this approach to drug discovery reignited the hopes of clinicians and patients alike. So much so, in fact, that Cummings himself broke protocol and put three of his own patients on the drug. When I asked him if he’d seen any changes, he gently exhaled down the line. ‘Well, one had very elevated triglycerides and so was only on it for a very short period of time. The other two continued for a few months and, you know, the families would do what they always do and say, “Oh, I think she’s a little better,” and then, “No, she’s getting worse.” In truth, I couldn’t see a definitive pattern. You just can’t know what’s happening because it’s such a slow disease and every patient has a slightly different course. So you cannot actually see whether you’re helping them or not.’

  Many of Cummings’ patients have become personal friends. With their time slowly running out, with the stepwise manner of science ceaselessly rewriting the rules of Alzheimer’s, they could not have asked for a more fearless pragmatist for their plight.

  When I began investigating bexarotene I was hoping to have a more conclusive idea of whether it would work. But it is, as yet, unclear how this research story will end. In a broader sense, the fact that a cancer drug can twist the cogs of Alzheimer’s inner gears says much about how we can approach the problem. It suggests that the web of causation stretches out into far more scientific domains than previously thought. Indeed, the stories of the last three chapters–of blood, prions and vision–vividly illustrate this point. While the challenge of describing Alzheimer’s must be drawn on hard, clearly defined lines, the challenge of treating it must remain conceptually malleable. This is the conclusion researchers are now reaching, and as a result many have begun testing the impact of other seemingly unrelated drugs–such as statins (primarily aimed at reducing blood cholesterol), anti-epileptic drugs (principally aimed at minimising epileptic seizures) and incretin mimetics (predominantly aimed to treat type 2 diabetes). All show signs of ameliorating the effects of Alzheimer’s in cell and animal models, and large-scale clinical trials are being discussed.

  The web of treatment is widening.

  PART V

  Discovery

  ON THE EVENING of 9 September 2012 Abbas went to sleep and never woke up. Aged eighty-two, his mind lost and his body frail, Abbas still needed help walking to the bathroom, and had a specially fitted hospital bed at his home in Tehran. His wife and three daughters, who’d been caring for him around the clock, stood ashen-faced as the doctor confirmed his death. After seven years of fear, confusion and profound loss, my grandfather was finally at peace.

  My father flew to Iran the next day. He had known Abbas was not long for this world and admitted to being somewhat relieved: the father who no longer recognised his family had calmly slipped away in the night. It was the best he could hope for.

  The doctors identified pneumonia as the cause of death. For all its cunning and unrele
nting work, Alzheimer’s isn’t what kills in the end. People die from the complications of Alzheimer’s: infected bedsores, broken skin and pneumonia can lead to sepsis and difficulty breathing; disorientation leads to a fatal fall; trouble swallowing makes a person choke on their food; some forget to eat altogether and suffer malnutrition. If a patient avoids all this, further complications set in, from stroke to heart disease to multiple organ failure. In its final act of forgetting, the brain forgets to tell the body how to stay alive.

  For a long time my father didn’t talk about Abbas’s death. When I asked him why not, he said it was because he felt as if he hadn’t done enough. He felt guilty as well as relieved. In many ways this is normal: guilt is a common product of grief, especially following the death of someone with Alzheimer’s. After years of seeing a loved one’s mind slowly disappear, it’s often the carer’s memories of exasperation and released frustration that come hurling back.

  But my father’s guilt came more from a feeling of inadequacy. He had been living and working in a foreign country for much of Abbas’s decline, and therefore couldn’t offer everything the family expected from a first-born son, which weighed heavily on him. He had seen television documentaries in which patients and relatives travel far and wide in search of answers. And now, looking back, he wished that he’d done the same. In researching this book, I thus made the decision to seek out researchers from the furthest corners of the earth and begin that search on his behalf.

  I knew of several places that warranted exploration.

  19

  To the Ends of the Earth

  What a piece of work is a man! How noble in reason, how infinite in faculty! In form and moving how express and admirable!

  In action how like an angel, in apprehension how like a god!

  William Shakespeare, Hamlet

  EVERYBODY KNOWS DR Stefánsson,’ said the driver as the taxi lurched across the snow. A bitter Arctic wind caked the windows in frost and a dimly lit sky hung overhead, the midday sun barely above the horizon. I’d come to Reykjavík in Iceland: a small, flat rock in the North Atlantic, whose inhabitants–not many, but some–are virtually immune to Alzheimer’s. How was this possible? And what did it mean?

  We pulled up at our destination. As I climbed out of the car, the driver added: ‘I haven’t given him my DNA yet. But I will soon!’ To Icelanders, I would learn, this kind of talk was pretty normal.

  On an August day in 1996 a tall, Icelandic, exceedingly philosophical man named Kari Stefánsson had an idea. A neurologist and pathologist, he’d seen countless Alzheimer’s patients–both dead and alive–and was beginning to tire of the slow, incremental and, in his view, erroneous approach to the problem. Biologists, he thought, could contemplate theories until the end of time, but they still wouldn’t have a concrete lead for drug companies to test. His belief was that not enough attention had been paid to a simple yet unalterable truth: the brain is hard-wired by genetics. Differences in the sequence of DNA’s four-letter code was the cardinal difference between Matthew and the wheat used at the Last Supper. It was the Holy Grail, Stefánsson insisted. And so, after twenty years toiling at American universities, he decided to return to Iceland with the singular purpose of eliminating common diseases by mining the genome of the Icelandic people.

  It wasn’t nearly as ridiculous as it sounds. With record low levels of immigration since the Vikings settled Iceland 1,100 years ago, the island’s genetically homogenous population made it a unique natural laboratory. It was to Stefánsson what the Galapagos Islands were to Darwin. Unlike Darwin, however, Stefánsson was going to need a lot more than wits and a notebook. He wanted to collect and sequence the entire Icelandic genome, some 300,000 people. The cost would be enormous–certainly more than any money he could obtain publicly. And to make matters worse, it was illegal for an individual to create their own database on healthcare; many saw it as a disturbing, Orwellian prospect. So Stefánsson set up a private company, called DeCODE Genetics, and lobbied the Icelandic government to change the law.

  He succeeded on both counts, and DeCODE immediately spread the word around Reykjavík and the wider community, asking anyone and everyone to give blood and/or saliva to help unlock the mysteries of human diseases. To ease the effort, the company sent out cheek swabs in the mail, telling people that a courier would come by to collect their sample, if they chose to give one. As an incentive, and to reach the remote villages outside the capital, the couriers were volunteers from the Icelandic Search and Rescue charity, which got a $20 donation for every sample it collected.

  Not everyone was enamoured by Stefánsson’s plan. Some saw it as an infringement of their private, most personal information. As one Icelandic journalist put it: ‘It makes me very nervous… in Iceland everyone knows everyone and when you give your DNA sample, you are not just giving information about yourself.’1 Stefánsson couldn’t have disagreed more. The way he saw it, a healthcare system was only able to treat people by using the information amassed from previous generations. How was it fair, therefore, for anyone to take advantage of such a system and yet simultaneously refuse people the right to help improve that system for future generations?

  He had a point. Critics had failed to appreciate that human samples were the lifeblood of medical advancements, not to mention optional and anonymous. Fortunately, many Icelanders did appreciate this. By 2004, 80,000 Icelanders had given samples; 120,000 by 2007, nearly half of Iceland’s population. The DNA sequencers could hardly keep up. To cope with the deluge, DeCODE installed colossal freezers containing gigantic car-manufacturing robots (one freezer contained half a million vials of blood) and supercomputers capable of holding 20 petabytes of data. To put that into context, it’s the equivalent of 10 billion floppy disks, or 10 trillion pages of text. But the usefulness of all that data paled in comparison to what turned out to be Iceland’s most precious resource: genealogy.

  Genealogy is a national obsession in Iceland. Almost every Icelandic saga begins with a lengthy description of family trees.2 Here’s one example: ‘There was a man named Ulf, the son of Bjalfi and of Hallbera, the daughter of Ulf the Fearless. She was the sister of Hallbjorn Half-troll from Hrafnista, the father of Ketil Haeng…’ And another: ‘There was a man named Onund. He was the son of Ofeig Hobbler, whose father was Ivar Horse-cock. Onund’s sister Gudbjorg was the mother of Gudbrand Lump, whose daughter Asta was the mother of King Olaf the Holy. On his mother’s side…’ And on it goes. Icelanders have done this for centuries. Stefánsson himself can trace his ancestry back to the Viking poet Egil Skallagrimsson, who lived in ad 900.

  This record-keeping has proved essential for the DeCODE project. Since DNA is inherited in chunks of code–vast stretches of ATCG, rather than being passed down in individual ‘letters’–many Icelanders’ genomes needn’t be sequenced. They could simply be inferred by combining family trees with clever computers.

  When Stefánsson put this strategy into action, the discoveries came in thick and fast. New genes underpinning heart attack, autism, schizophrenia and many cancers were unearthed, as well as genes influencing smoking behaviour, skin pigmentation and even creativity. The discoveries made headlines coast to coast, and Stefánsson was enshrined in Time magazine’s top 100 people transforming the world. I remember the day I first heard about him. I was sitting in the lab, waiting for an experiment to finish, frustrated by how slow and inefficient academic research can often be. His success was bewitching. He was a maverick, a misfit, a rebellious pragmatist, unencumbered by politics and fully aware that curing big diseases requires big data and big capital. In 2012 the US pharmaceutical giant Amgen kept his dream alive by purchasing DeCODE for a little over $400 million. For Alzheimer’s research, this was all a prologue to another vital clue.

  On 2 August 2012 Stefánsson published data showing that about 1 per cent of 1,795 Icelanders carry a genetic mutation shielding them from Alzheimer’s.3 Astonishingly, it was found in APP, the same gene underlying Carol Jennings early-onset.
But where Carol’s mutation was due to a ‘T’ that should have been a ‘C’, the Icelanders’ mutation was a ‘T’ that should have been an ‘A’. This tiny genetic fluke had the effect of shifting beta-amyloid into reverse gear: while Carol’s brain became saturated with amyloid, the Icelanders’ brains produced half the usual amount. It was resounding support for John Hardy’s amyloid hypothesis, and an olive branch to pharmaceutical developers, now weary of constantly having their fingers burned by this lead.

  But the mutation also hinted at some deeper, primordial truths–about ageing and why Alzheimer’s even existed.

  ‘I’ll give you an example of how strange memory is,’ Stefánsson offered, seated in his spacious office at DeCODE’s headquarters in the suburbs of Reykjavík, the imposing Hallgrímskirkja Church spire and craggy visage of Mount Esja visible from the window. ‘When I was seven years old, I went to an old movie theatre located exactly where this building is. The movie was The Scarlet Pimpernel. Then, about thirty years later, I was in Chicago taking my daughter and her friend to the movies. On the way back, the following verse suddenly popped into my head: “Is he here or is he there, the French are seeking everywhere, is he in heaven or is he in hell, the elusive Scarlet Pimpernel”. I haven’t seen that movie since I was seven… Where does this come from?’

  Just shy of seven feet, Stefánsson is a Herculean man, with ice-blue eyes and thick white hair. His father was an author and radio journalist, disappointed by his son’s resolve to pursue science instead of writing. Stefánsson still remembers the summer night in 1968 when he and a classmate drank through the night, talking about life, purpose and the world of alternatives to choose from, before applying the very next day to medical school. Now, aged sixty-six, his childhood cinema recast as a genetics super-lab, he wakes every morning and comes into work feeling as if he’s ‘playing in the sandbox’.