In Pursuit of Memory

by Joseph Jebelli

  The letter was addressed to St Mary’s Hospital in London, where a group of researchers were chasing a lead many considered a long shot: could Alzheimer’s be genetic?

  This radical idea had started to gain traction when Leonard Heston, a physician in Minnesota, published some astonishing observations in October 1981.1 Using brain samples from over 2,000 post-mortems done in Minnesota state hospitals, he’d found that relatives of middle-aged, or ‘early-onset’, Alzheimer’s patients were more likely to develop the disease when they reached middle age themselves. Even those with self-confessed ignorance of genetics knew this had the earmarks of inheritance; indeed, Heston wasn’t the first to suggest the link: physicians in Sweden and Switzerland during the 1950s spotted the trend while looking through hospital records of families with a history of dementia. At that time, however, genes were thought to be entities that only gave rise to basic aspects of human biology such as height, build and eye colour. They certainly weren’t believed to have much (if anything) to do with the intricate vagaries of the mind. In any case, genes were still inaccessible molecules and so physicians were more interested in the chemical basis of disease.

  But by the 1980s the DNA double helix had come and gone and gene sequencing technology was well on its way. George Glenner, a molecular pathologist at the US National Institute on Aging, seized upon Heston’s results.

  Quiet and reserved, formal and aloof, with wavy silver hair and an unassuming gaze, Glenner didn’t know much about the brain when he began working on Alzheimer’s in 1983. He was considered an outsider by many neuroscientists. After training at Johns Hopkins University he quickly became fascinated by how diseases develop at the cellular level, and therefore chose to specialise in pathology. In particular, Glenner was puzzled by amyloid–which he called ‘one hell of a nasty substance’2–and soon became hell-bent on figuring out what it really was.

  Glenner’s mission epitomised the confidence that targeting the plaques was medicine’s best bet. No one actually knew if they caused the disease, nor whether they formed before or after neurons started dying. And no one knew if they were more or less culpable than the tangles seen inside neurons. Nevertheless, their lingering presence demanded answers; disproving their significance became just as imperative as proving it. With access to freezers filled with donated brains–one of the first Alzheimer’s ‘brain banks’–Glenner set to work, mechanically slicing and grinding up each one, uprooting blood vessels, sifting out connective tissue, and chemically pulverising what was left until nothing but amyloid remained. After a year–in May 1984–he’d finally managed to extract the protein that formed the plaques’ core, and dubbed it beta-amyloid, a term that would resonate among neuroscientists for the next thirty years.3

  Glenner then performed a quantum leap. In Heston’s study it had been noted that many Alzheimer’s patients’ relatives had a high incidence of Down’s syndrome in the family. Doctors were realising, moreover, that nearly everyone with Down’s syndrome who reached middle age invariably died with a dementia uncannily similar to Alzheimer’s. The conditions clearly had some sort of connection, but what was it?

  Down’s syndrome, a genetic condition that develops from an abnormal extra copy of chromosome 21, was the only other known condition where vast deposits of amyloid saturate the brain. And when Glenner began examining amyloid from Down’s syndrome patients, he realised it was made up of the same protein found in the brains of Alzheimer’s patients.4 This suggested something wholly unexpected. Maybe, for some people, there was a gene for Alzheimer’s–lurking somewhere inside chromosome 21.

  And so as soon as Glenner’s results were released, scientists started gathering DNA samples from families showing signs of an inherited form of Alzheimer’s, which they called ‘familial’ Alzheimer’s disease. One sample came from a large family of Canadians of British origin, whose ancestors emigrated to Canada in 1837; in just eight generations a whopping fifty-four cases of Alzheimer’s had been reported. A German family had twenty cases in six generations. A Russian family showed twenty-three cases in six generations. A large Italian family, whose members had branched out to France and the US, had forty-eight cases in eight generations.

  Familial Alzheimer’s looked identical to the more common, non-inherited version; the only noteworthy difference was the age of onset: its symptoms appeared much sooner, usually in people’s fifties, forties and even late thirties. The discovery of familial Alzheimer’s was revolutionary not only because it proved Alzheimer’s could be genetic, but because its genetic origin offered scientists the first real clue as to how the predominant, late-onset disease manifested. With a gene as their starting point scientists could investigate what other molecules it interacted with, and thereby begin to stich together a biochemical web of causation. It was akin to pinning a photograph of a Mafioso on a drawing board for detectives then to map out the entire crime syndicate.

  By 1986, acting on Glenner’s findings, several US groups successfully decoded the DNA sequence of beta-amyloid.5 They christened the gene APP (for amyloid precursor protein). That gave the scientists-cum-detectives a suspect. But APP by itself wasn’t enough. They needed to learn if the gene was guilty by finding out if it had been permanently altered from what was normal. And for that, they needed to find a mutation.

  Tall and brunette, with thin, sparrow-like features and narrow, enquiring eyes, Carol Jennings was an extremely conscientious woman who knew a problem when she saw one. Her father, Walter, was the eldest of fifteen children born into a working-class Protestant family. A milkman who’d served in the navy during the war, Walter was a scrupulous man who worked hard to look after Carol, the apple of his eye. He was known for his chatty, high-spirited temperament and the thorough way he managed the family’s finances, constantly writing things down and chasing up monthly dues from the Nottingham Co-op.

  By his fifty-eighth birthday, however, Walter was becoming ‘a different person’–quiet, disengaged and strangely no longer able to organise his accounts. Sometimes he seemed genuinely befuddled by even the most routine of tasks: while shopping he would often pick up the wrong things and then put them in somebody else’s trolley. When the family took him to a doctor they were told he had dementia, probably Alzheimer’s. There was no discussion about a cause or even his disproportionate age.

  But Walter was not the only one: four of his younger siblings started experiencing symptoms as they approached sixty themselves. Ironically, because lots of the family were getting Alzheimer’s this early, many of them thought it was quite normal. But not Carol, whose letter soon found its way to St Mary’s Hospital. And there, working in a laboratory, was a twenty-eight-year-old molecular geneticist named Alison Goate.

  Goate was part of a large group searching for Alzheimer’s mutations. ‘Everybody acknowledged that there were these families with Alzheimer’s that appeared to be genetic,’ she told me in her lilting, transatlantic accent during a call from New York, where she now works as director of the Mount Sinai Alzheimer’s Research Center. ‘But these families were extremely rare, so people didn’t really talk about genes for Alzheimer’s at the time.’

  Energised by Carol’s story, St Mary’s immediately responded saying they wanted to know more. They arranged for doctors to ask questions and collect blood samples. And so Carol contacted the entire family, asking them all to meet at her house to donate samples and tell the doctors everything they knew. ‘I was always impressed by Carol,’ Goate said. ‘She was like a cheerleader the way she persuaded family members to participate.’

  Back in London, the hunt for the gene mutation was on. It relied on exploiting a key principle of genetics: genes that sit close to one another on a chromosome tend to be inherited together–they are said be genetically linked. This meant that if certain chunks of DNA were always seen in a family with a history of dementia, one could infer that a mutation was hiding somewhere in that region of DNA. If the proverbial DNA search engine worked, it promised a new era of personalised medi
cine. Treatments targeting a genetic defect could conceivably fix the problem’s root cause, blowing drugs like tacrine out of the water. ‘The acetylcholine drugs are approved because there’s nothing else,’ Goate said. ‘They may be better than nothing for some people, but they’re treating the symptoms rather than the cause. But your genetic predisposition might suggest which drugs you should be taking.’

  Still, finding a mutation wasn’t easy. Although DNA is a simple molecule of four repeating chemical groups–Adenine (A), Thymine (T), Cytosine (C) and Guanine (G)–its code is 3 billion letters long in humans. Written out, it would amount to 200 volumes each 1,000 pages long, which would take a typist grinding eight hours a day half a century to complete. How could anyone expect to find a spelling mistake in that? Fortunately, the Down’s syndrome connection and the whereabouts of the APP gene gave Goate a good place to start: chromosome 21.

  Just four years later, in February 1991, Goate found the mutation.6 It was a single letter of DNA code–a ‘T’ that should have been a ‘C’. Three billion letters and that’s all it took to dismantle Carol’s family. If there’s any field that makes one truly appreciate the knife-edge we live on, genetics is surely it.

  The discovery provoked a blizzard of media attention. FAMILY LINK OFFERS HOPE OF ALZHEIMER’S DISEASE CURE, declared The Times. GENE MUTATION THAT CAUSES ALZHEIMER’S IS FOUND, hailed the New York Times.

  In the wake of the discovery, Goate and some colleagues visited Carol and her family in Nottingham, where they had all congregated in Carol’s living room. They were eager to know what had been found and what it actually meant for them. Goate explained that the mutation is what geneticists call fully penetrant: anyone who carries it will definitely develop early-onset Alzheimer’s. It was also dominant, meaning they all had a 50 per cent chance of carrying it. Then came the crux: there was a test. Anyone who wanted to know could do so, including Carol. Both choices were reasonable. Knowing meant she would be free of worry were the test negative, or could plan the rest of her life accordingly were it positive. Then again, not knowing meant living without the burden of such knowledge were it positive.

  There’s a name for this kind of dilemma. It’s called a ‘Hobson’s choice’, after the sixteenth-century stable owner who had a stable of forty horses but only ever offered his customers the horse nearest the stable door. The choice is thus an illusion because only one option really exists, and you can take it or leave it. So, would you want to know?

  There was a time, during my PhD, when I was offered the chance to know if I would eventually develop Huntington’s disease. A friend was studying it for her own thesis and was interested in how it affected blood. For this she needed blood from healthy volunteers, and I donated without fully realising she would, obviously, have to check that I really was a healthy volunteer. After the phlebotomist withdrew my blood I was handed a form asking if I wanted to be informed if it tested positive. Granted, the chances of me having it are next to zero; the condition is hereditary and no one in my family has ever had it.

  But I still said no. Huntington’s, like Alzheimer’s, is a cruel and devastating condition. It causes erratic, uncontrolled movements and cognitive impairment that steadily descends into a nightmarish dementia all of its own. There is no cure or treatment in sight. And so the only thing worse than succumbing to the disorder, in my mind, was knowing I would succumb to it years beforehand.

  Carol, too, said no. She didn’t see the point in knowing when there was nothing she could do about it anyway. In August 2012, healthy but approaching her family’s age of onset, she told a reporter: ‘I never did want to know. Having the test has always been an option: I could find out now. But I think I would just collapse in a heap if I thought, “This was it.”’7 After Walter died she’d devoted thirty years to Alzheimer’s awareness and research. Drug companies flew her around the world to give talks about what it was and how it affected her family. And every year she volunteered for brain scans, helping scientists amass an invaluable record. Because the research was always double-blinded, even the researchers remained oblivious to Carol’s ambivalent genetic fate.

  ‘My nan had fifteen kids. I mean, you can’t even imagine that, can you?’ Carol said, with a quiet laugh and a shake of her head. It was early in the afternoon of 18 September 2015. I was sitting in the living room of a modestly sized house on a narrow, leafy avenue in Coventry, England, talking to Carol and her husband, Stuart.

  ‘I’m trying to think who else had it,’ Stuart said, while handing me a cup of tea. He was fifty-nine years old, a university chaplain and historian, with deep-set eyes and a soft, cherubic face. ‘Let’s think, Carol. Your aunty Audrey had it. Your uncle had it. Kath’s got it at the moment but I think that’s age-related Alzheimer’s.’

  ‘Yes, oh yes,’ said Carol, in a softly spoken voice freighted with compassion. ‘And did you know, my nan had fifteen kids. You can’t even imagine that, can you?’

  Carol was diagnosed in December 2012. She was fifty-eight years old: the same age her father, Walter, started displaying symptoms. According to Stuart, there had been noticeable lapses in her memory and cognition since 2008. ‘You can’t live with somebody for thirty years and not notice slight, subtle changes.’ Carol kept forgetting what she’d gone into a room for, he said. Then she began storing numerous items of clothing, inexplicably, beneath her pillow. They didn’t seem like particularly serious mistakes at the time. ‘Carol would say to me, “The trouble with you is that you’re looking for it.” But things weren’t right.’ At work Carol had become uncharacteristically disorganised, missing deadlines and forgetting to file paperwork. Again, little things. But that was just the start–a slow accrual, carrying her mind gently and irrevocably towards the baffling ailment that plagued her father.

  While the three of us chatted, she pointed at a black and white picture of Walter resting on a nearby wooden cabinet. He had a thin, rugged face, wore thick rectangular glasses, and was neatly dressed in a white-striped shirt and tie. I asked if she remembered what made her write the letter to St Mary’s all those years ago.

  ‘There was something…’ she mused, furrowing her brow. ‘For a while things were going… a bit pear-shaped… there was some sort of thing, I’m sure, that was… a little bit… strange.’

  As I sat there, listening intently, seeing how a slip in just one gene is expressed in the vicissitudes of personhood, I was struck by how acutely unaware of Alzheimer’s Carol had become. Here, in front of me, was a woman who had transformed our understanding of the disease, a woman who had devoted most of her life to raising awareness of it. Now, she was scarcely able to say its name.

  Then she chuckled. ‘I mean, the family my nan had got, how many kids did they have? Fifteen, wasn’t it?’

  ‘Your grandma did, yeah,’ Stuart replied. He said this in a calm, dispassionate way–not impatiently or patiently–just in the way he always spoke to his wife. He wasn’t going to let the disease change that.

  We finished our tea and went to have some lunch. We ate back in the comfort of the living room, exchanging anecdotes and shifting the conversation to jocularity, Carol naturally being fairly quiet but smiling just the same. Afterwards, she went upstairs to see her ninety-year-old mother, Joyce, who lived with the couple and was now, incredibly, helping care for Carol. Joyce was quite healthy for her age, according to Stuart, and of course knew all about the condition after caring for Walter thirty years earlier.

  Now alone with Stuart, I asked him frankly: how was he coping? He explained how he teeters from stoicism to despair. He said he once knew a woman who got on a plane to Bern, Barcelona and Buenos Aires, a woman who travelled the world to speak at conferences to neuroscientists and the public. But now, he said, ‘I wouldn’t trust her to walk up the road to the grocery store.’ Stuart is fighting to save Carol; every few months the couple make the trip to London to try the latest experimental treatment. But Carol is fading and he knows it.

  ‘I think it’s too late for Car
ol,’ Stuart confessed. ‘It’s the kids we’re fighting for now.’

  A few weeks later I met John Jennings, the couple’s thirty-year-old son, in his apartment amid the bewitching dark stone buildings of Edinburgh, Scotland. He was tall and thin, had dark brown eyes, and resembled Carol. An exceedingly thoughtful man with a quiet seriousness of purpose, John had become increasingly involved in raising awareness since his mother’s decline. Her affliction is something he’s all too familiar with, for he now faces the same terrifying odds she did.

  ‘Because it’s always been there it’s a huge part of who I am,’ John said, recounting the media attention and intense scientific interest in his family during the early 1990s. As a child, he didn’t think anything was particularly amiss with his grandfather. Walter was an old man as far as he was concerned; his affliction–whatever it was–was simply his way of dying. ‘I remember visiting him in the ward. He would just sit in this huge padded chair.’ John remembers seeing his mum, who was never good with needles, passed out on the couch after the St Mary’s team took blood samples–including his. Only when John reached adulthood, however, did the profundity of his family’s situation, and the stark decisions he would have to make, finally sink in.

  Did he want the test? ‘I’ve chosen not to know,’ John confided in me with a philosophical tone. ‘Because Mum always used to say, “You know, you could get hit by a bus,” and part of the human condition is that you plan as though you’re gonna live for ever. But I’ve sort of convinced myself that I have the gene, which is quite common to people from these families; we assume we have it, and if it turns out we don’t it will be a bonus.