In Pursuit of Memory Read online

  Raised on the wooded outskirts of a small town in central Missouri, Summers is a very different breed of scientist. His pragmatic yet unorthodox approach seems to have run in his family: both his father and grandfather were physicians and the young Summers, who was expected to follow in the family tradition, would often accompany them to the local hog-rendering plant to collect pig thyroids. The family would hang and dry the thyroids in their garden and then harvest the extract to treat patients with hypothyroidism–an effective method that was eventually replaced by synthetic means. Summers first became interested in Alzheimer’s while training in psychiatry at Washington University in St Louis, when the idea of Alzheimer’s as a form of dementia was beginning to take hold.

  However, Summers remains unconvinced by the popular idea that plaques and tangles cause the disease. ‘I think they just mark where the dead neurons are,’ he told me, during a long conversation in the office of his private practice in Albuquerque, New Mexico. ‘They might cause some neuronal death, but I think for the most part they’re actually protective mechanisms against other things. There are probably more than fifty different targets and Alzheimer’s is just the result of a final common pathway.’ For Summers, acetylcholinesterase is the target–and tacrine the ideal weapon.

  In February 1981 he administered the drug to twelve Alzheimer’s patients intravenously.11 The doses varied–after all, no one had any idea what amount would be effective, detrimental, or even fatal. But for all the suspense and trepidation the results were remarkably positive. Nine patients showed significant improvements in cognition only a few hours following treatment. And the side effects were mercifully limited to mild nausea and excessive sweating. ‘It impressed me,’ said Summers, ‘that a toxin can, in the proper circumstances, become a medicine.’

  Summers was eager to push his study further, but others in the hospital remained sceptical. As a full-time clinician at the University of Southern California the majority of Summers’ working day was spent seeing patients, which left little time for research. Determined to pursue his research, Summers left the clinic and went into private practice: ‘I thought what the hell, I would go earn money in the private sector, pay for my own research, and who gave a damn what they thought at the NIH!’

  A straight-talking and resolute man by nature, Summers spent $90,000 out of his own pocket–$300,000 by today’s standards–to develop a tacrine pill with the help of a few supporters at the University of California, Los Angeles (UCLA) and the Aldrich Chemical Company in Milwaukee. Mice and primates underwent testing, the US Food and Drug Administration (FDA) approved human trials, and by 1986 Summers published the results of seventeen patients given the drug orally in the New England Journal of Medicine (NEJM).12

  His findings were an instant sensation: the drug did appear to temporarily improve memory and cognition in Alzheimer’s patients. It wasn’t a cure, but for the millions watching loved ones slipping away, the beacon of light it offered was blinding. ‘The genie was out of the bottle,’ said Summers. ‘There was a Saudi prince who had Alzheimer’s and they were going to send a jet to LAX to pick me up and take me to Saudi Arabia to treat the prince. I had no idea what I was playing with to be honest.’

  For all the excitement, though, there were many doubters. One troubling issue for the FDA and fellow neuroscientists was that Summers did the study out of his private psychiatric practice, under his own steam, out of sight of the academic establishment. This raised suspicion. Indeed, other researchers failed to replicate the result. Before long, Summers found himself embroiled in a year-long federal investigation.

  ‘There’s a rule of invention,’ he told me, ‘the lion’s share of invention takes place in the wrong place, by the wrong people, at the wrong time, for the wrong reasons. I fit all of those. The discovery of the first treatment for Alzheimer’s should certainly have come from the NIH, not from an individual in private practice in LA, and it should’ve come from big government grants, not from somebody who’s self-funded on a shoestring.’ The NEJM article, said the FDA, was overstated and misleading. According to them, there were gaping holes in the techniques and conclusions, reflecting an additional failure on the part of the NEJM reviewers.

  Eventually, Summers was vindicated. A special committee of faculty at UCLA, charged with scrutinising his work with a fine-tooth comb, told the FDA that it checked out and on 10 September 1993 tacrine became the first FDA-approved treatment for Alzheimer’s disease. As more patients started enrolling in the treatment it became clear that the effects–though positive–were modest. But it was enough to bolster hope in the idea that the disease would, and could, yield to treatment–something many in the broader scientific community never thought possible.

  Today there are four internationally approved drugs for the treatment of Alzheimer’s: Donepezil (AriceptTM), Rivastigmine (ExelonTM), Galantamine (RazadyneTM), and Memantine (NamendaTM). The first three work using the same scientific principle as tacrine. Patients who take them usually show a delay in the worsening of their symptoms for about six to twelve months–allowing them to cope better with simple daily tasks like dressing, shopping and personal hygiene. Whether you agree with Summers’ somewhat renegade methods or not, he was a trailblazer for modern Alzheimer’s research. His work created a desperately needed inroad of hope in a world with Alzheimer’s disease rapidly on the rise. More importantly, his efforts signalled the first major assault on the disease that was based on a scientific, evidence-based hypothesis, giving other scientists the confidence to assert their own mechanistic theories. Would he do it again? ‘Yeah, I’d do it in a heartbeat. Look at the people who have hope and are getting benefit. So it was worth every battle.’

  We have entered a very different world from the one Summers and his predecessors entered. Their study of Alzheimer’s taught us that memory is a material phenomenon, a subtle and exquisite product of healthy brain cells. They taught us that if memory resides anywhere, it resides in a network of durable connections and neurotransmitter systems between those brain cells. And if the rhythms of a damaged heart could be exposed and repaired, then so could memory. They had demonstrated that Alzheimer’s could be abolished.

  PART II

  Research

  FOR MY FATHER, the suspicion that Abbas was sick came during a phone call in the winter of 2003. My aunt Masoumeh had noticed that Abbas had forgotten where he lived. For weeks, she said, Abbas was either walking to the old family home in north Tehran, only to be turned away by its new residents, or he circled a nearby park, trying to piece together the details of his true address. When he did remember his way home, moreover, his wife Afsana was turning him away because he had been calling her ‘Parry’–his first wife’s name. My father encouraged her to take Abbas to the doctor. He knew how difficult the old man could be, but Abbas was behaving like a tourist in his own neighbourhood, and he had been ‘newly’ married for eighteen years.

  Until then I still believed that Abbas’s behaviour was normal and assumed that wouldn’t change. But when my father put down the phone that day I knew that things were different. He booked a flight to Iran the next day.

  Eight years later, I sat with my father at a dinner for Persian New Year in a hotel in central Bristol. A group of elderly Iranian expats were sitting on the next table, laughing, sipping tea, chatting about friends and family.

  ‘You know, Dad,’ I said as the waiter poured our drinks, ‘I can’t really remember a time when Granddad was like that.’

  ‘You were young. He was a very sociable man before his Alzheimer’s.’

  ‘How did you find out he has Alzheimer’s?’

  ‘We took him for memory tests and a brain scan and the doctors said it was probably Alzheimer’s.’

  ‘Probably Alzheimer’s,’ I said, surprised by the flippancy of the description. ‘What else did they say?’

  ‘Not much, only that it was very difficult to know for sure.’

  I wondered if that was still the case. At the time, I had j
ust completed the first year of my PhD and was too busy learning how to tease apart molecules to give diagnosis much thought. Besides, that was the province of medics, not scientists. I belonged to the crowd studying the brain from the inside looking out, not the outside looking in. But now, I wanted to know. I wanted to meet someone at the very beginning of their descent and understand how we first lock horns with the disease, and what this means to those as confused as I once was. I also wanted a closer look at how our present understanding of the disease was reached. What did my colleagues and other scientists think caused it? Where were we in terms of an effective treatment?

  What follows is a critical and impassioned journey to answer such questions, and a look at the surprising human stories that gave us this deeper understanding. Sometimes I worried that my persistence might have got the better of me; that in undertaking this endeavour I was reminding my father of a painful time in his life. But it was okay, he said. Everyone should grow old like those expats–laughing, sipping tea, chatting about friends and family. Sharing our experience is how we get there.

  4

  Diagnosis

  One loyal friend is worth ten thousand relatives.

  Euripides, attributed

  ONE MORNING IN late 2014 Arnold Levi, an eighty-two-year-old retired film director from South Africa, walked into his local doctor’s clinic in London with his best friend’s son, Danie. The pair had known each other for more than thirty years; Danie’s father had grown up with Arnold at a boarding school on the outskirts of Johannesburg. Arnold was sent away to school at the age of five, and he and Danie’s father had instantly bonded. ‘My dad was one of three brothers,’ Danie told me. ‘I think Arnold loved him because they protected him at school. They treated him like family.’

  Something had been wrong with Arnold for nearly a year. In December 2013 Danie noticed some unsettling changes in his behaviour. Intelligent, self-reliant and streetwise, Arnold almost never had any trouble navigating the London Underground; every few months he would get the Tube from his home in west London and travel into the city to meet Danie for dinner.

  But things began to change. Arnold seemed increasingly distressed by the journey, Danie recalled. One day, when they met outside the station, he appeared ‘flustered’, ‘agitated’, ‘cross’. It wasn’t like him, said Danie.

  When Arnold was twenty, he moved to London to pursue his dream of becoming an actor. He played small parts in several films but soon changed tack when a colleague asked him for help teaching singers how to act. Arnold agreed, and enjoyed a fine career directing thereafter. He never married and had no children, but always stayed in touch with his childhood friend back in Johannesburg. Twenty years later, Danie moved to London for work as a stockbroker. ‘When I moved here I lived close to Arnold, and he always watched out for me. “If you ever need a place to stay,” he’d say, “you can always stay with me.” I always knew that support was there.’ As Arnold got older, Danie watched over his father’s old friend in the same way.

  In the months leading up to that day on the Tube, Danie began to spot problems with Arnold’s memory. At first they seemed minor: he forgot his passport for a flight to New York, for example; he forgot that Danie had been on holiday. Typical things. But something about their frequency and nature felt atypical. Only in retrospect is Arnold’s experience unsurprising. During the incipient phase of Alzheimer’s symptoms, it is just about impossible to know that such lapses indicate the disease. ‘My memory’s shocking,’ Danie told me. ‘Literally, I can’t remember what I did on the weekend. I just don’t have the bandwidth to retain it. So when somebody else doesn’t remember something you’re not particularly surprised. But it was these little situations that just… jarred. They weren’t normal. They didn’t sit right.’

  Danie arranged a private car to collect Arnold for their next outing. But when the driver arrived at the house, Arnold wasn’t in. The driver called Danie, who then called Arnold. No answer. Earlier in the week, when Danie rang to arrange the lunch, he remembered that Arnold had kept misunderstanding the instruction and thought he was supposed to meet Danie where he used to work–a studio in north London. ‘I said, “No no, the driver’s gonna pick you, so don’t go anywhere, yeah?” But he just kept on. I was thinking, what is it about the bloody…? Just stay at home! You don’t have to do anything! You’ll just be delivered here. What’s wrong with you!?’ Danie tried calling the house an hour later. Again, no answer. Now he was getting worried. He called the studio–Arnold was there.

  It turned out he’d had no memory of ever discussing being collected by a private car. Danie told him not to worry, and asked if he felt comfortable getting a cab to the right location. He did, and so Danie, somewhat relieved, tried to put the mishap down as another harmless ‘senior moment’.

  His relief was short-lived–Arnold didn’t arrive. Two hours later, he rang Danie from home. ‘He called me and said, “Listen, I’m sorry, I don’t know what happened… I think I’ve had a turn… I didn’t know where I was… But I came across a Tube station and got myself home.”’ Later, Danie discovered that Arnold had forgotten what to do after leaving the studio and, confused, had then spent the time aimlessly wandering around the city. At that point, the young South African knew that he needed to take him to a doctor.

  As they walked through the corridors of the Richford Gate medical practice–a wide, three-storey, sand-brick building occupying a quiet residential street in west London–a German physician called Jens Foell greeted them. Unexpectedly, Arnold introduced Danie as ‘Mathew’, Arnold’s neighbour. They laughed it off, and went to take a seat in Foell’s office. Already suspecting what might be wrong, Foell politely asked how he could be of assistance.

  So Arnold said, ‘Well, it’s Mathew—’

  ‘No, Arnold,’ Danie interrupted, ‘it’s me, Danie.’

  Arnold continued: ‘He’s been having some trouble.’

  There was a momentary silence–and Foell, now unsure which of the two men was the patient, looked towards Danie.

  ‘Arnold,’ said Danie, ‘we’re here for you.’

  ‘Oh really?’ Arnold replied. ‘I had no idea.’

  In August 2015 I caught the London Underground to Arnold’s house in Notting Hill, with a bag of fresh grapes and a box of Swiss chocolates. It was a warm, cloudy afternoon, with streets full of people eating lunch alfresco, hoping to see the sun. I had first heard of Arnold several months earlier through a medical colleague. I’d asked if he knew any newly diagnosed patients willing to share their story. I wanted a classic case, I’d said–unaware then just how frail the term ‘classic’ is for Alzheimer’s–and he’d responded by providing Danie’s phone number. When I then called Danie, he was keen to talk to me. He said he felt alone.

  Before entering Arnold’s home, Danie briefed me outside. He had explained to Arnold who I was and why I was visiting–although he had to admit the likelihood that Arnold really remembered was slim.

  We rang the doorbell. For a minute no sound emanated from the house, and, it being a holiday weekend, Danie feared Arnold might have wandered off somewhere unchaperoned. A moment later, however, the door opened and I was introduced to Arnold. He had curly white hair, glacier-blue eyes, and a broad, unabashed smile that instantly put one at ease. He was thin and willowy, casually yet smartly dressed in a dark purple shirt, check shorts and pointed leather shoes. He offered me a drink, which I politely refused, and the three of us sat down in a sitting room off the kitchen.

  Ceiling-high windows flooded the room with natural light, Middle Eastern rugs blanketed the floor, old wooden dressers held ornate antique statues, and eighteenth-century artwork hung from every wall. Works on Mozart, Michelangelo and Wagner filled his bookshelves, as well as titles by Dickens and G. A. Henty. Here lived a man utterly devoted to learning, I thought. How cruel it was that this too would soon be taken from him; a love of books and knowledge made it all the more painful to lose one’s memory. And beside me, arranged on his desk, we
re framed black and white photographs of his parents, and Danie’s father, in Johannesburg. It was like stepping into a time capsule whose keeper has left a small simulacrum of himself.

  We started talking. He spoke slowly, his voice low and sonorous, with an acquired English accent poles apart from Danie’s clipped South African twang. I asked him questions about his life and friendship with Danie and his father. I asked him about his career, and the stories behind some of the beautiful objects surrounding us. His answers were eloquent and enlightened; he was clearly a highly intelligent man. Indeed, if we’d kept with this line of conversation I wouldn’t have noticed anything was amiss. I then began asking him about the present. What were his neighbours like? Did he have friends living nearby? This is where things started to unravel.

  ‘It’s funny you should ask that,’ Arnold said, ‘because that was during the war… but I don’t like going down this road.’

  I changed topic and asked what he liked to do during the day, now that he was retired.

  ‘I had to look after my mother and sister… this was during the war of course… but that isn’t a very fit subject.’

  Danie chimed in: ‘Arnold, I think what Joseph was actually asking you was what do you like doing today.’

  ‘Oh yes, of course, my apologies. Well, I was always very keen to live on my own. I couldn’t wait to get out [of South Africa]… and don’t forget, it was the end of the war… I would offer you something to drink but I don’t think I’m going to.’