In Pursuit of Memory

by Joseph Jebelli

  ‘And because I’ve had so long to build a way of dealing with it, I don’t have the all-gripping fear that a lot of people have. Even though Mum was really upset when she first had something resembling a diagnosis, she’s happy enough at the moment. So, from her perspective, it’s sort of… okay.’

  As anyone would be, John’s now keen to discover where the mutation came from. Carol’s great-grandmother, a woman born in 1861–just a few years shy of Alzheimer himself–was the earliest known carrier, he explained. But more than anything, he wants to know what his ancestors’ lives were like. He’s amazed at how the family’s symptoms are being re-enacted with an almost hallucinatory quality: at Carol’s wedding, for example, Walter got confused and told people that his daughter was getting married soon–Carol did the same thing at her daughter’s wedding; and Walter often followed Joyce around the house–which, according to Stuart, is now exactly what Carol does as well.

  John then switched on his laptop to show me a Facebook group for other people confronted by early-onset dementia. One conversation thread described a single mother who’d recently tested positive and was wrestling with the decision whether to tell her fifteen-year-old son. Another told of three young siblings, two of whom possess a mutation that will initiate the disease in their late thirties. John replies to them all; the crucial thing, he says, is to keep talking about it.

  When I asked John how much he talked to his own family about it, and what those conversations were even like, he gave me a wry smile and laughed. ‘We’ve actually got this middle-class British problem of not talking about anything of any kind of emotional import. We still do that; we’ll skirt around the issue. Even if something comes on the news about dementia, we’ll watch it in silence and then discuss what comes on afterwards.

  ‘We did once speak about what it would be like,’ he offered, recollecting a wine-fuelled evening while on holiday with his parents some years earlier. ‘We said that it would be like watching a television screen and the static slowly increasing.’

  Confronted by a 50 per cent chance of that analogy eventually becoming reality, how much did he think about it? ‘More or less every day,’ he admitted. ‘I wake up in the night sometimes and think about it. But then I’ll think about the fact that we’re losing Mum, which is a weird kind of grieving process, losing somebody over a long period of time. And then I feel guilty because it’s something she’s experiencing and I’m just worrying about. So there’s a lot of different ways it enters your consciousness.’

  On the plane back to London I tried to make sense of Carol’s story. A spate of unanswerable questions filled my head. How would I feel if my grandfather’s Alzheimer’s was familial? Would I have said ‘no’ to that test? What if John had changed his mind and learned he was positive before Carol got sick? Would her right not to know have obliged him to secrecy? Could you even keep something like that from your parents? And what did this form of Alzheimer’s say about human existence? Are we prisoners of our genes?

  Then I remembered something Stuart had said to me just before I left their home. ‘If we were to have a poem that encapsulated our way of thinking about this, it would be Dylan Thomas’s “Do Not go Gentle into that Good Night”. Because we’re not giving up. And all the research and the press… well, it’s just our way of saying, “Fuck you, we’re having the last word.”’

  And they will. Recognised as the first discovered cause of Alzheimer’s, the APP mutation gave scientists the evidence they desperately needed. No longer did they have to guess if amyloid was responsible, now they had tangible proof. There was still much work to be done: scientific discoveries generally take about twenty years to ascend the throne of clinical and commercial use. That time would be filled sketching separate but no less urgent explanations, such as how tangles fit into all this, and whether a medicine based on APP would help people with non-genetic, late-onset Alzheimer’s. But there was no doubt, the field had moved up a gear. Today, thousands of scientific papers have been published as a result; each one a small, incremental discovery bringing us closer to a cure; and each made possible because a curious milkman’s daughter sat down to write a letter.

  6

  The Science Behind the Headlines

  DEMENTIA AND ALZHEIMER’S LEADING CAUSE OF DEATH IN ENGLAND AND WALES

  Guardian headline, November 2016

  AND THERE IT was. Confirmation of what many had feared. The headline reached numerous broadcasts and, thanks to colleagues, appeared numerous times in my inbox, like an alarm I couldn’t switch off. Alzheimer’s had now overtaken heart disease as a leading cause of death in my country and one of its closest neighbours. Citing a report by the Office for National Statistics, the author quoted an increase from 13.4 per cent of all recorded deaths in 2014 to 15.2 per cent in 2015.1

  Reading the article, I was torn: as a patient relative, I felt sorrow but also relief: That’s terrible, though maybe now people will do more about it. As a scientist, both emotions yielded to anger: It should not have got this bad! Clearly an effective treatment was now urgent. Of course, not a week goes by when the news doesn’t declare a breakthrough with the spectre of a cure. The irony is that the ceaseless headlines reflect how much we don’t know, rather than how much we do.

  People often ask me, ‘What is Alzheimer’s disease?’ I respond with an explanation of plaques and tangles, cell death and memory loss. But by the end of the twentieth century, the real question was where did Alzheimer’s come from? How did it start?

  Three remarkable theories emerged and neuroscience adopted a new mantra: Alzheimer’s disease is a process.

  As a science obsessed with small changes occurring over long stretches of time, it seems apt that genetics would be the field to usher in this concept. The marriage of disciplines hatched a hybrid called neurogenetics: a special branch of genetics focused solely on the brain. It also ushered in a new armada of neurogeneticists. Among them is John Hardy, the most cited Alzheimer’s researcher in the UK. Hardy has been working on dementia since the days of Kidd and Terry, when only a handful of people on the planet were focusing their research efforts on the disease. An avuncular, plain-speaking man, he has an almost celebrity status among his peers, and is often seen wandering the corridors of his laboratory in University College London in shorts and flip-flops, a stack of papers under his arm, poking his head over the shoulders of young academics, eager to see what the new generation of researchers are up to.

  In 1992 Hardy put forward a bold new theory on the cause of Alzheimer’s, one that was to prove so alluring, so self-evident and so impressive in its scope that since then an explosion of work has emanated from it. ‘In all cases of Alzheimer’s disease,’ he told me during my visit to his office, ‘we have amyloid plaques scattered throughout the brain. In all cases we have tangles inside neurons. In all cases we have nerve cell loss. And in all cases we have a dementia. As scientists we have to work out which of those things is first. We have to put an order to them.’

  And that’s exactly what he did. Hardy argued that the formation of beta-amyloid plaques in the brain is the primary event in the disease. Tangles, neurotransmitter loss, cell death, memory loss and dementia, he said, are all secondary events–brain flotsam and jetsam left by a harrowing and crippling storm of amyloid. He called his theory the amyloid cascade hypothesis,2 a hypothesis he confidently asserts is ‘no question, the best idea’. He and his supporters are known as the Baptists (from Beta Amyloid Protein)–a highly appropriate name given the fervour of their belief in it.

  Though beta-amyloid’s function is still unknown, biochemists agree that it looks like a protein with responsibilities at the cell surface. Cell surface proteins often act like molecular drawbridges for the cell, permitting the entry and exit of other molecules. Alternatively, they can act as molecular antennae for communication with neighbouring cells. If one of these proteins malfunctions–due to a genetic mutation, say–the cell might self-destruct to stop the damage leaking into the cellular circu
itry protecting us from cancer. At this level, life is ruthlessly totalitarian.

  To play out Hardy’s hypothesis, then, malfunctioning fragments of beta-amyloid first drift away from the neuron and accumulate as plaques. Over time, these plaques grow in size to the point where normal neuronal communication is no longer possible, like islands of waste preventing maritime trade. Starved of biochemical support, conditions inside the neuron start to break down–cue the tangles–and the neuron soon does what evolution has instructed it to do. It kills itself.

  Exactly how beta-amyloid triggers such a neural catastrophe is, Hardy admits, a complete mystery. ‘We don’t know. I mean, we really don’t know. And I would say that’s the biggest hole. We just don’t understand how plaques kill neurons.’

  The theory had two key advantages. First, it put Alzheimer’s disease on a temporal plane. Framing it this way meant scientists could make testable predictions about the disease’s trajectory and evolution. Second, it gave drug companies another target to complement acetylcholine. The meagre effects of acetylcholine-based drugs created a dire need to try something new and left a gaping (and lucrative) hole for pharmaceutical companies to fill with new, amyloid-based therapeutics.

  Families like the Jennings were a source of major support. ‘Because we’d found families which had amyloid mutations,’ Hardy explained, ‘that told us that, in those families anyway, amyloid is where the disease starts. So the simplest thing to assume is that amyloid always starts it; that it’s always the first event.’

  Proof of Hardy’s theory arrived when a group of researchers at Athena Neurosciences, a San Francisco-based biotechnology company, did what was long considered impossible. On 9 February 1995 Athena’s scientists injected mouse embryos with a human APP gene mutation.3 The idea of a mouse possessing human DNA is too strange to contemplate. Suffice it to say, the invention broke new ground by providing a means to actually breed the disease ad infinitum.

  So did these animals really get Alzheimer’s? They certainly developed plaques in their brain, and showed cognitive impairments in memory-related tasks such as navigating a maze. But strangely, they didn’t show any signs of tangles–nor, for that matter, a great deal of cell death. It was as if they had partial Alzheimer’s. But the fact that Carol Jennings’s mutation–a mutation leading to excessive beta-amyloid production–caused the animals’ downfall provided strong evidence for Hardy’s amyloid cascade hypothesis. It didn’t prove the theory, but it might as well have, his supporters proclaimed. After all, no model is perfect. In an editorial in Nature the same year, Hardy boldly stated that the generation of amyloid plaques in these mice ‘settles this argument, perhaps for good’.4

  Working in Hardy’s laboratory is an invigorating experience. In the years following my grandfather’s diagnosis, reading scientific literature had left me awash with ifs, buts and maybes. Nearly everyone I told–family and friends alike–returned looks of soft commiseration: ‘That’s what happens when you get old,’ they’d say over and over again. Working alongside Hardy, I felt grounded in my quest for a better answer.

  But not everyone shares Hardy’s conviction that beta-amyloid marks the start of Alzheimer’s disease.

  As dusk descended on a cool and clear April evening in 1984, Allen Roses, a neurologist at Duke University, North Carolina, waited anxiously at a railroad crossing, watching the cars of a passing coal train gently rattle by. The train was a rare sight. But of all the days it could appear, on that particular day it was most unwelcome. Standing next to him was a colleague, and in between them, lying on a wheeled stretcher, was an elderly woman with Alzheimer’s, who had been pronounced dead only thirty minutes earlier. They were taking her from the hospital, down a narrow concrete track, to a post-mortem facility less than 300 yards away.

  Roses didn’t usually have to run an urban obstacle course as part of his day; his normal routine involved sitting at a lab bench. But that day was different. Roses’ boss wanted him to head a new Alzheimer’s research programme and so Roses submitted a grant application to the National Institute on Aging and was swiftly rejected. If Roses wanted the money, the NIA said, he would have to prove that he could get patient brain tissue from the hospital to the lab in less than one hour.

  So as the train sluggishly rolled along the track, Roses and his colleague could do nothing but wait. When it finally passed, the pair dragged the stretcher the rest of the way as fast as they could. As they pushed through the doors to the post-mortem suite, they immediately checked their watches: forty-one minutes. They had done it.

  Over the next few years Roses joined the hunt for an Alzheimer’s gene, and by 1990 he had identified a genetic variant for late-onset Alzheimer’s.5 (Variants are not the same as mutations: whereas mutations often directly cause disease, variants simply increase a person’s risk of disease. They are commonly dubbed ‘genetic risk factors’.)

  Meanwhile, one of Roses’ colleagues, a neurologist named Warren Strittmatter, was busy trying to wrap his head around a perplexing technical issue with his experiments. Strittmatter, like George Glenner before him, was an amyloid expert. Whenever he purified amyloid from patient brains, however, he kept fishing out another protein stuck to the plaques. It must be a contaminant, he thought. But Roses wasn’t so sure, and asked him to pursue the lead and identify the substance. Four months later Strittmatter discovered that it was apolipoprotein (APOE), a decidedly uninteresting liver protein that carries fat and cholesterol in the blood and can be found throughout the body. It probably had nothing to do with Alzheimer’s.

  But in that moment Roses had an epiphany. He knew the APOE gene was located on chromosome 19, the same chromosome in which his latest work had flagged up a new Alzheimer’s gene. Was the connection mere coincidence? Roses didn’t think so. His team, on the other hand, almost certainly did. They refused to do any more experiments on it, convinced, as Roses later put it, that ‘the chief was off on one of his crazy ideas’.6

  But Roses kept digging. He learned that the APOE gene exists in three versions–APOE2, APOE3 and APOE4–and became struck by the possibility that one of these versions might increase the risk of late-onset Alzheimer’s. The best way a version could be distinguished from the others was by a burgeoning technology called polymerase chain reaction (PCR). Invented in 1983 by the American biochemist Kary Mullis, PCR is essentially a DNA photocopier. It allows scientists to amplify tiny amounts of DNA for the purposes of paternity testing, forensics and medical diagnostics.

  Although PCR is easy to perform, it helps to have an experienced hand. And so, ostracised by his team, Roses turned to his wife, Ann Saunders, a mouse geneticist well versed at PCR. By spring of 1992 the couple had unearthed a truly startling finding. APOE4 carriers have a high risk of developing both early- and late-onset Alzheimer’s–fourfold higher if one copy of the gene is inherited, twelvefold with two copies. The gene is present in 30 per cent of the population and, astonishingly, in 50 per cent of all Alzheimer’s patients, making it the leading genetic risk factor for the disease.7

  But how could a liver protein be involved in Alzheimer’s? At scientific conferences, where passions run high, the criticisms launched at Roses ‘went from nasty to vicious’, he recalled. But despite the scepticism, Roses persevered.

  On 14 November 1995, at a debate over the motion ‘This house believes beta-amyloid deposition causes Alzheimer’s disease’, he fired back. He presented a slideshow displaying three photographs. The first photograph was of a Japanese Shinto grave, an elaborate and complex work of art; the second was of an old tombstone found in a Catholic cemetery; the third was his father’s grave, a bronze plaque in a Jewish cemetery. He pointed at them and said, ‘Every one of these is absolutely diagnostic of what’s underneath it. But nobody would say that the tombstone caused the death.’

  But the analogy did little to dissuade the disbelievers. His intention, though, was not so much to dispel interest in beta-amyloid as it was to receive acknowledgement of APOE4. ‘I have no doubt th
at there is plaque formation,’ he assured me. ‘I just don’t think it’s the cause. But everybody in the Alzheimer’s community thought APOE4 was a big joke. They just didn’t want to hear about it. I couldn’t even get another grant to pursue it.’

  Listening to Roses, I felt both sympathetic and inured to his plight. Scientists are not the paragons of mutual camaraderie we might imagine them to be–all hell-bent on uniting under one banner to seek the truth. They are human. Big intellects bring big egos, which partly explains why Roses was dismissed by so many. Although a string of European studies soon confirmed his discovery, by 1997 the Alzheimer’s community was firmly focused on the amyloid cascade hypothesis. Unable to fund further work on APOE4, Roses was forced to leave academia and pursue the lead in the pharmaceutical industry. There, he pioneered a new theory on the cause of Alzheimer’s, one that put APOE4 in the spotlight and which came to be called the mitochondrial-impairment hypothesis. Or more simply, ‘type three diabetes’.

  In type one diabetes, problems arise when the death of insulin-producing cells in the pancreas depletes the body of insulin. Type two diabetes, on the other hand, results from insulin resistance when cells stop responding to it following an excessive dietary intake of glucose (although genetic and lifestyle influences are also thought to be involved). In type three diabetes, the theory goes, the APOE4 gene somehow interferes with normal blood sugar uptake in the brain, thereby depriving the brain of the energy it needs to fuel cellular activities. Proof for it came in late 2000, when two psychiatrists–Eric Reiman at the University of Arizona, Tucson, and Gary Small at the University of California, Los Angeles–used brain imaging to show that people who have the APOE4 gene metabolise glucose at lower rates than people carrying the APOE2 or APOE3 versions.8 Roses’ followers don’t have a nickname, but let’s call them the ‘E4ists’.