In Pursuit of Memory

by Joseph Jebelli

  I didn’t anticipate how much the disease exerts its influence completely under the radar, in a hidden and nebulous incubation period that scientists are only now beginning to comprehend. My understanding of the illness that robbed my grandfather of his twilight years was morphing and expanding into something totally different. A look into Zetterberg’s lab changed the picture even more.

  As we walked down the hall we passed an enormous piece of modern art. It depicted bolts of liquid flowing from a brain into a test tube, painted in bright hues of blue and orange. Stepping into the lab, it was clear what captured the artist’s imagination. The entire room was abuzz with the sound of electronics and mechanics, unrecognisable contraptions the size of vending machines skirted the walls, and streams of polychromatic fluids fizzed through vast networks of clear hollow tubes.

  ‘So here we have two robots,’ Zetterberg said, pointing out two robotic arms injecting liquid into tiny plastic wells. I remember doing this technique by hand as a researcher; it was trying, to say the least. A technician was standing nearby, supervising the robots’ progress. She told me the robots get through 200 samples of spinal fluid a week, half of which flag up a positive signal for Alzheimer’s–or rather, future Alzheimer’s. Testing people now doesn’t make a lot of sense. With no cure or proven lifestyle countermeasure, little good can come from telling people they have a high chance of a harrowing illness. But Zetterberg thinks this will change in the future. ‘That’s why I really feel like we are prepared for the event of therapies,’ he explained. ‘In the future, when we get effective treatments, people in their forties or fifties will want to know. They will go to their physician and say, “My father had Alzheimer’s and I would not like to end up like that. Could you please tell me if I’m biomarker positive or negative for the disease, and give me the treatment if I’m positive.” I really feel like this is a realistic future.’

  Zetterberg then introduced me to Dzemila, a young technician charged with organising all the data the robots churn out. Every day she trawls through hundreds of results for anonymised patients all around the world. ‘There’s someone from Sydney,’ she says, pointing at the list on her computer screen. ‘Prague… Copenhagen… Wisconsin… I don’t like this list. I get panicked.’ For Dzemila, it’s not the disease but rather the exploding number of cases that frightens her. A single person’s biomarker test takes seventeen minutes, she told me. The reason it’s only performed on suspected Alzheimer’s cases is because it simply wouldn’t be ethical (until a proven treatment is found), not to mention feasible, to test everyone. I wondered whether I’d want the test; Alzheimer’s was, after all, in my family.

  Leaving Dzemila to her onerous list, Zetterberg and I continued the tour. He showed me robots testing spinal fluid by the femtolitre (that’s one thousand million millionths, or quadrillionth, of a litre). He showed me machines the size of small cars searching for biomarkers–our brain’s neurological message in a bottle, it seemed. He spoke quickly, using wonderfully bizarre terms like secretomics and electrochemiluminescence.

  I was amazed that humans were capable of building something like this. These tortuous amalgamations of tissue and technology were practically cybernetic organisms, with crystal balls for hearts. Then Zetterberg showed me the most important part of the lab, the biomarker discovery section–a bank of tall black boxes, each pulsing neon blue and green lights. It looked more like an NSA data centre than a neuroscience lab. Here, Zetterberg’s machines are delving even deeper, looking for molecular clues besides beta-amyloid and tau, in mediums beyond spinal fluid. The problem with spinal fluid, Zetterberg explained, is that it requires an often painful lumbar puncture; it’s too invasive. Blood is the next obvious choice because it’s easily accessed, thus patients can be tested and followed over several years. He’s already demonstrated proof of concept with his ice hockey concussion study. Now, others are extending this to Alzheimer’s.

  In March 2014 a group at Georgetown University, Washington DC, led by a neurologist called Howard Federoff, showed that differences in the levels of ten kinds of blood fats could predict whether a person is destined for Alzheimer’s.3 The changes were identifiable three years before symptom onset and were also 90 per cent accurate. In November of the same year Dimitrios Kapogiannis, an NIH researcher, claimed that defects in a blood-borne insulin protein called IRS-1 could predict Alzheimer’s ten years in advance.4

  But there are pitfalls. The numbers of patients enrolled in these studies were small, usually in the hundreds. Biomarkers are also hard to detect when submerged in four litres of blood (compared to 150 millilitres of spinal fluid). And the signals kept vanishing because substances alien to blood are quickly cleared.

  Scott Turner, another Georgetown neurologist, suggested a more left-field approach in late 2013. At a conference that year he announced that Alzheimer’s might be detectable in the eye. Using Alzheimer’s mice he found that the retina–a light-sensitive layer of neurons at the back of the eye–was up to 49 per cent thinner than that of healthy animals.5 This extraordinary finding made headlines and may make more if it’s replicated in humans. As one investigator observed at the time, ‘It would be great if we could simply look into someone’s eyes to see if they had Alzheimer’s, but unfortunately spotting the disease is a lot more complicated than that.’6

  Still, it’s a start, and a very necessary one at that. After all, biomarkers promise much more than early diagnosis: they can turn drug development on its head. Because Alzheimer’s unfolds gradually, effective drugs might work subtly and over lengthy stretches of time, making it hard to verify their true potency. A biomarker that reflects small biochemical changes could therefore reveal how well the drug is doing along the way. Whatever the outcome of biomarker research, my time in Zetterberg’s lab made one thing abundantly and inexorably clear: this is one of the most exciting avenues of Alzheimer’s research today.

  Before I left Gothenburg, Zetterberg had one last thing to show me. It was something close to his heart, something that took him back to his childhood. We took a taxi from the hospital and drove towards the outskirts of the city. The streetlights receded in the distance and the light grew thicker in the wintry fog. We were heading to a government-funded nursing home in a borough called Frölunda, where the Swedes are experimenting with a new way of caring for Alzheimer’s patients. I shouldn’t say patients, though; that word has no place here. Here, they are residents.

  We pulled up outside a white, modern, three-storey building, not far from the botanical gardens and the Göta älv River. Inside, Marika Mattsson, a member of staff casually dressed in a white shirt and jeans, welcomed us. After shaking hands, I glanced around the foyer and noticed something rather odd: there wasn’t a uniform in sight. In fact, the place looked more like someone’s house than anything else. Ninety-six residents live here, half of whom have dementia, the majority caused by Alzheimer’s. It’s one of many facilities scattered across Sweden to deal with the country’s ageing demographic.

  The Swedish government has served its citizens’ longevity well. In recent years, the country pledged 4.3 billion Swedish krona to improve healthcare for the elderly, and Sweden now has one of the highest life expectancies in the world. By 2035 it’s estimated that one in four Swedes will be over the age of sixty-five, and a 2013 United Nations report ranked Sweden the best country in the world for quality of life among the elderly (the UK ranked thirteenth; Afghanistan was the worst).7

  Wandering the halls with Mattsson, it’s easy to see why. The rooms are furnished with the tenants’ possessions. Scores of kitchens and living rooms ensure that each only has six people in it at a time. There’s a bakery, an art studio, a gym, even a spa (with a sizeable jacuzzi). What a contrast, I thought, to the asylum where Alois Alzheimer worked.

  But it’s the home’s ethos that really makes the difference. The job of the staff here, as Mattsson sees it, is to give the residents a surrogate for their actual home. ‘The key word is tranquillity,’ she explained.
‘We use small groups because we want to make this feel like a real home. And that’s exactly what it becomes for many tenants. Sometimes, because they don’t remember, we actually replace their relatives–we become their father, their mother, their brother, their sister, their old friend from school.’

  Strolling into one room, Mattsson introduced me to a group watching a black and white movie. Some looked reasonably engaged; they were asking a young man sitting beside them to explain the movie. Others, of course, did not. According to Mattsson, many think they still have jobs to go to, and often dress and pack each morning in order to continue the careers they once had.

  Also present were two relatives who introduced themselves as Annika and Mona and immediately invited me for coffee. Annika’s seventy-five-year-old mother, Marie, has lived here for the past year, her symptoms having advanced beyond what the family could manage at home. They noticed symptoms eight years ago; in those days they’d find her fridge filled with exactly the same food products (twenty pieces of cheese for example). Marie also appeared to be storing money and personal possessions in clothes hanging in her wardrobe. Such innocuous idiosyncrasies soon transformed into indisputable omens when she began asking for her long-deceased mother and father. ‘They’re dead! Don’t you know!?’ Annika would reply in exasperation.

  During her diagnosis, Marie underwent spinal fluid analysis, contributing to the first generation of patients receiving biomarker testing for Alzheimer’s. Originally from Finland, Marie had moved to Gothenburg in her twenties and worked in a bakery before marrying a Swedish steel worker and settling down to raise Annika and her two siblings. In their mid-sixties, when the children had grown up and left home, Marie and her husband moved into a small three-bedroom apartment, ready to enjoy grandchildren and indulge in their long-sacrificed pastimes.

  For Marie, that pastime was painting. Through her working years, she always maintained that she would one day paint the flowers she saw in magazines, routinely cutting out the pages portraying her favourite specimens. But by the time she’d bought a canvas and fashioned a palette, her symptoms forbade her from brushing a single stroke.

  ‘I’m so mad at her for never painting,’ said Annika, pouring herself another coffee. Her voice was calm and tender but frequently took on a hard-edged quality, as if the years watching her mother fade had inured her to Alzheimer’s. She wasn’t sad any more; she was angry. ‘Now she’s got hundreds of magazine clippings and dozens of canvases, and she keeps saying, “Oh I want to paint, I want to paint.”’

  I wondered what Marie’s paintings would look like. I remembered the paintings of William Utermohlen, the American artist who lived in London. In 1995, upon learning that he had Alzheimer’s, Utermohlen began painting a series of self-portraits. For five years he painted his face, each picture blurrier and more abstract than the last. The result was a staggeringly expressive portrayal of his descent into dementia, and the paintings were widely exhibited. But ironically, the very act of painting may have slowed his descent. Painting stimulates the parietal lobe, a region involved in creativity and one that remains intact until quite late in the disease. In the 2014 documentary I Remember Better When I Paint, therapist Judy Holstein explains:

  We know that [patients] take in colour, form, shape… and it translates in an Alzheimer’s person’s brain to have some meaning. The creative arts are an avenue to tap into a non-verbal, emotional place in a person. When they’re given paint, markers, any kind of media for art making, and their hands are involved, and their muscles are involved, things are tapped in them that are genuine and active and alive. So the creative arts bypass the limitations, and they simply go to the strengths.

  ‘I’ve tried to paint with her,’ Annika continued, ‘but she can’t do it. She can’t do anything any more. She spends all her time packing, because she thinks she’s going home.’

  The aim in Sweden is to keep the elderly and infirm at home for as long as possible. Independence, family and familiarity are seen as the best–if only–ways to preserve the mind and slow cognitive decline. Those who stay at home receive government aid, like home-delivered cooked meals. Some of Sweden’s municipalities even arrange for small teams of elderly people to meet and cook together. The downside to this approach, of course, is that by the time people like Marie enter nursing homes they are heavily entrenched in their symptoms. In the opinion of Mattsson, this is problematic because many tenants then take at least six months to settle in. ‘Today they’re coming to us much later. The average age is between eighty-five and ninety, closer to ninety. When they come here they’re so ill, so far into their dementia. And in the final stages of dementia you can’t bond with people the way you once could, so it’s harder to integrate them.’

  To help Marie adapt to her new life in the home–and not wanting to see his wife exit life in fear and confusion–her husband has moved in with her. She doesn’t recognise him, despite being married for fifty-six years. ‘When she talks about her mother, my father just looks at me and sighs,’ said Annika. ‘She likes to sing Pavarotti. She keeps saying she will marry him. I say he is dead and your husband is sitting right there–don’t talk about Pavarotti.’ We all laughed. There’s undoubtedly a droll kind of humour to Alzheimer’s. It’s often the best way to cope.

  Fortunately, Marie’s mind has yet to erase the memory of her children. And there are other things to be hopeful about. As she ventures through what the American essayist Susan Sontag called ‘the night side of life’, ‘the kingdom of the sick’,8 Annika’s mother–whether she knows it or not–played a small part in helping to decrypt Alzheimer’s with biomarkers, and belongs to a society that cares for its night-side citizens with the wisdom, dignity and respect they deserve.

  For the first time in my journey I sensed victory. Everything I’d learned about Alzheimer’s represented mere snapshots of a process that evolves over decades. Up to this point, time had remained dementia’s most intractable and elusive quality. But time, the murky borderland between health and disease, was the key. It may be simultaneously Alzheimer’s great strength and Alzheimer’s Achilles heel. And in Zetterberg’s quest to exploit it, he was using it against Alzheimer’s. He was doing what Shakespeare prescribed in King John:

  Be stirring as the time; be fire with fire;

  Threaten the threatener and outface the brow

  Of bragging horror.

  He was turning the disease in on itself.

  When we dream of a cure for Alzheimer’s, we usually envision a pill for when symptoms appear. We forget that as our understanding of the disease is increasingly defined and adjusted, so too must our methods for defeating it be redefined, readjusted. It seems the bottom line in the world of drugs, science and medicine is that we need to spot the disease earlier. But what about the ordinary world? Are there lifestyle measures we can harness as well? Can we, in short, push it back ourselves in our daily lives? I wanted an answer.

  PART III

  Prevention

  MY GRANDFATHER WAS not one for self-gratification. In the Islamic Republic of Iran he couldn’t drink even if he’d wanted to. My father told me that he ‘probably had six whiskies in his entire life, one for each time he visited us in England’. He kept fit, waking every morning at 5 a.m. to go hiking in the foothills of the Alborz Mountains in northern Tehran. He didn’t smoke. And he had a good diet, eating plenty of fish, pomegranates, pistachio nuts and the vegetable-infused, rosewater-scented stews typical of Persian cuisine.

  He lived a predominantly stress-free life too. A property developer in the affluent province of Shemiran, Abbas had inherited a fortune from his own father, Shaban, a logger and well-known figure in Tehran. Abbas was therefore free of financial worries, and in truth didn’t need to work.

  All told, my grandfather’s decidedly salubrious life sheds little light on the cause of his illness. And this, I was beginning to realise, was a recurring theme: Arnold, the cultivated and bookish South African I met in London, lived a healthy life, as had Car
ol, the upbeat and proactive early-onset patient from Coventry. So what–if anything–destined a person towards dementia? More and more it was looking like the Californian neuroscientist Arthur Toga was right when he replied simply ‘bad luck’, in response to the same question posed by Terry Pratchett in 2008. Sardonically, Toga went on to say that ‘this is an equal opportunity disease’.

  But as I read the studies on lifestyle countermeasures–and there are many–it became clear to me that there is still cause for hope. Though much of the evidence is preliminary and inconclusive, and sometimes merely anecdotal, considerations for stress, diet, exercise, cognitive training and even sleep are gaining scientific ground. And so I stepped into the uncertain world of preventive healthcare with cautious optimism.

  9

  Stress

  There is more to life than increasing its speed.

  Mahatma Gandhi, attributed

  IN HIS TRAILBLAZING work The Stress of Life, published in 1956, endocrinologist Hans Selye explained how stressful experiences can make us sick. Before Selye, the notion that stress could influence our biology was practically unheard of. Today, we’re all too familiar with the toll modern-life stress exerts on our health. Depression and anxiety, headaches, insomnia, heart disease: the evidence linking them to stress is overwhelming. Whether stress also contributes to Alzheimer’s isn’t as clear-cut, but once scattered and now mounting reports are giving weight to the idea.