In Pursuit of Memory

by Joseph Jebelli

  We know that genetics is central to understanding this disease, and that while only a small minority of people inherit genes for early-onset Alzheimer’s–genes such as APP and PSEN1–many of us possess genetic risk factors that can tip the balance towards dementia, with the APOE4 gene being the strongest risk factor. Undoubtedly, the genetics of the twenty-first century will add a great deal to this story.

  But we also know that Alzheimer’s is going through a drastic reformation of underlying principles. In the past decade, as methods to conceptualise brain function have advanced, a more holistic understanding of the disease is taking shape. Perhaps the most insightful thesis on this so far–‘The cellular phase of Alzheimer’s disease’, by Bart De Strooper and Eric Karran in 2016–argues that the advent of ‘systems biology’, a method using sophisticated statistics and clever computers, should soon provide the means to generate ‘a comprehensive cellular theory of the disorder’.3 By drawing on individual discoveries from the broad canvas of cell biology, biochemistry, molecular genetics and neuroimaging, this approach may have the power to piece the entire puzzle together. Just as the Human Connectome Project seeks to map all the neural connections in the brain, systems biology may yield an ‘atlas that describes the evolution of Alzheimer’s disease’, they write.

  Detection is another transformative development. Rather than focusing on the ultimate destruction of the brain, our lens has swung 180 degrees, pointing instead at the early, telltale signs of a brain in decline. Even as I write this, a study showing that proteins in human tear fluid might indicate Alzheimer’s has reached my desk.4 Biomarker findings such as these will continue to move the bull’s-eye for treatment to middle age, if not younger. And while lifestyle countermeasures have yet to be unanimously approved, we do know that an increasing number of experts are encouraging their use every day. I could probably fill a textbook with all the neurochemical processes we’ve had to reorganise and reimagine. Alzheimer’s research, the scientific field once viewed as a fool’s errand, has transmogrified into the grandest of pursuits.

  Attitudes still need to change too, of course, for an ageing society can engender as much defeatism as it can defiance. There’s an uncomfortable comparison worth mentioning here, which is that cancer, while causing a similar number of deaths each year, receives on average ten times more funding than Alzheimer’s. Eliminating cancer is vital, but we shouldn’t pour all our efforts into one pandemic only then to be met by another–vanquishing the devil only to meet the deep blue sea. The situation is starker still when comparing Alzheimer’s funding to that of HIV/AIDS. In the early 1990s the public lobbied US Congress to allocate 10 per cent of its research budget to help those with the infection. Consequently, it’s now a manageable disease and the number of deaths has fallen from 45,000 per year in 1995 to 7,000 in 2013. And yet, the US hasn’t readjusted its budget; Alzheimer’s receives less funding even though it’s now a much bigger problem.5 This makes no sense. Research funding should reflect disease burden.

  On a simpler note, we need more research into the biology of healthy brains. We all marvel at our ability to build cities and skyscrapers, to appreciate art and music, to comprehend planetary motion and organic evolution, to explore the world’s oceans and send objects into space, but for all our accomplishments we still don’t understand how the organ responsible for such accomplishments works–or why, with time, it breaks down. As the line between Alzheimer’s and ageing is further discerned, a better apprehension of the brain’s normal inner workings will be crucial to stop the latter spawning the former.

  The good news is that people are waking up. In the UK in 2012 former Prime Minister David Cameron launched the ‘Dementia Challenge’, a government initiative committed to more than doubling research spending on Alzheimer’s, from £26.6 million in 2010 to £66.3 million in 2014. In America, Congress has also agreed to boost Alzheimer’s funding by 50 per cent, approving a $350 million increase in its 2016 budget. In Europe, private industry is joining public–private schemes such as the European Prevention of Alzheimer’s Disease (EPAD) initiative, which aims to create a register of 24,000 people for longitudinal studies and clinical trials. And around the world, big drug companies like Johnson & Johnson, Roche and Novartis are coming back to the table, investing $3.3 billion in research in 2014, according to Forbes magazine, more private funding than in any of the preceding ten years.6 In the end, it all whittles down to money.

  Perceptions are also changing. Listening to Fox, I couldn’t help noticing the age group of the audience. I’d expected to see mostly middle-aged people, mothers and fathers caring for their elderly parents, perhaps. But these people looked between eighteen and thirty. When I asked some of them why they’d come, it turned out it was for the same reason I decided to write this book: to learn what happened to their grandparents. Fox’s campaign was working. A new generation of neurodetectives was here, curious to find the truth.

  It was surely this curiosity that provoked a critical moment in not just Alzheimer’s but all realms of biology: CRISPR (or Clustered Regularly Interspaced Short Palindromic Repeats) was little more than a repetitive sequence of bacterial DNA when it was first spotted by Japanese scientists in the 1980s. But in 2007 it was discovered that CRISPR is in fact a clever molecular defence system protecting bacteria from viruses: when a virus attacks, CRISPR first stores a fragment of the virus’s DNA in the bacterium’s genome, recording the threat, and then uses that information to delete any DNA with the same sequence.

  Over the past few years, scientists have figured out that CRISPR can also be used as a gene-editing tool for humans. That’s because CRISPR is composed of two parts: an enzyme called Cas9, which deletes the viral DNA, and a ‘guide’ molecule, which ferries Cas9 to the correct location in the genome. By artificially altering the guide molecule, scientists can theoretically add or remove any DNA sequences they want. The technology is in its early days, but the transformative effect it will have on medicine is staggering. Picture it: you go to your doctor and are then referred to a geneticist, who informs you that your son has cystic fibrosis but that they can simply delete the causative gene and replace it with a healthy one. It will be as if he never had the disease. Or you walk into a clinic with an untreatable and inoperable type of cancer, but the geneticist can use CRISPR to edit your immune system’s DNA to spot and destroy the malignant cells. And of course, the geneticist could explain that you have the APOE4 gene, that it’s a strong risk factor for Alzheimer’s, and offer you an APOE2 instead. While discussing that, they could even offer to screen and edit any other genetic risk factors for Alzheimer’s as well.

  Film enthusiasts will have already drawn parallels to the 1997 film Gattaca, a futuristic drama about a world where gene-editing technology has reached its zenith, and, as a consequence, every child has their genome sequenced and edited at birth, ensuring a long and disease-free life. I am not overstating matters when I say that CRISPR is the first inroad towards such a future.

  When this day comes, and it will come, there will doubtless be ethical issues concerning designer babies: parents may want to modify genes linked to intelligence, physical strength, behavioural traits, even sexual preference–conceivably leading to another narrative in Gattaca in which the technology inadvertently triggers a new form of genetic prejudice and career discrimination, what philosopher Philip Kitcher calls ‘laissez-faire eugenics’. It won’t be easy to determine where to draw the lines, but as long as we proceed with caution and integrity, that reality should remain unthinkable.

  When Fox’s speech was over, I wandered through the rest of the exhibit. There were scores of cheerful, energetic researchers showcasing Alzheimer’s-themed activities and games for the public. One activity was a giant ‘memory wall’, on which people had written their most enduring memory. I glanced over some of them. ‘Getting engaged in the Sahara desert,’ one person had written. ‘Burning my feet on a beach in Greece,’ wrote another. ‘Having my hair brushed by my mum whilst looking
at a blue car.’

  In a room next door people were playing a retro-style Alzheimer’s arcade game, saving virtual brain cells by shooting the killer proteins beta-amyloid and tau. There was a game called ‘Operation Alzheimer’s’, a huge plastic mould of DNA that people had to repair by switching genes on and off. There were stem cell scientists displaying pictures of brains in a dish, physiotherapists discussing the impact of sports and head injuries, neuropsychologists waxing lyrical on Terry Pratchett and visual Alzheimer’s. And on and on. Alois Alzheimer would have been stunned.

  The most encouraging research right now is the amyloid-based treatments. In August 2016 the US biotech firm Biogen released some early clinical trial results for their new antibody drug, Aducanumab, designed to clear amyloid-beta using the brain’s immune cells. For 165 mild Alzheimer’s patients, following a year of monthly injections, the drug reduced beta-amyloid levels and slowed cognitive decline. Such news also bodes well for Big Pharma’s new BACE inhibitor drugs, designed to stop amyloid accumulating in the first place. The challenge now is to recreate such victories in larger trials. As for the other research areas quickly gathering pace–tangle research, neurogenetics, stem cell technology, young blood, prion biology, off-label cancer drugs, visual Alzheimer’s, lifestyle influences–the outlook is good, in that they will either donate key insights to sharpen the blade of amyloid therapeutics, or launch a volley of specialised medications for those who don’t respond to such treatment.

  I hadn’t planned to write a book that involved so many separate strands of thought and areas of research; that ended so open-endedly. The pragmatist in me believed there was only one true path on the road to a cure, and that if I could only find it, I would have the answers I so desperately sought. But now, walking through the exhibit, I suddenly understood why it had to be this way. There was no single path, no one idea to pursue indefinitely. The march of each idea provided the footing for another. And only when enough ideas converge shall we ever reach the summit. As Sir Edmund Hillary once said, it is not the mountain we conquer ‘but ourselves’.

  Coda

  There seems something more speakingly incomprehensible in the powers, the failures, the inequalities of memory, than in any other of our intelligences.

  Jane Austen, Mansfield Park

  IN MARCH 2016 I arranged a final meeting with Carol and Stuart Jennings. They’d taken the familiar trip from Coventry to London for another round of experimental treatment, and kindly set aside some time for me. More than a year had passed since I’d seen Carol. I wasn’t quite sure what to expect.

  ‘There’s been a slight decline,’ Stuart said while the three of us sat in a restaurant near Russell Square. ‘Otherwise things have been okay, haven’t they, Carol?’

  ‘Hmm yes… oh yes,’ she replied with characteristic buoyancy. But Carol had undoubtedly slipped. She was quieter, less engaged, more withdrawn. She depended more on Stuart to steady her thoughts. When it was time to order, Stuart led the way while Carol softly echoed fragments of what he said, her mind seemingly taking refuge in his.

  I kept remembering something Stuart had said to me when I was at their house. He’d told me that when they were young, as a new couple discovering each other, he rode a clapped-out old motorcycle. I pictured a young Carol sitting on the back, gripping on to Stuart, ready to start their life together. Even now, she was holding on to him, I realised, unaware of her destination but knowing the journey was important. When so much of a person’s memory is stripped away, watching their loved ones hold on to and love what’s left is a lesson in true intimacy.

  ‘It’s her language and conversation that’s deteriorated the most.’ Stuart lowered his voice several octaves, still uncomfortable speaking of Carol in the third person. ‘There are moments of lucidity, where you suddenly realise the person’s still there, somewhere… But the reality is that when you’re with someone for so long, you don’t need to communicate. It’s been forty years since we met. We know each other so well. There are things which are said but unsaid.’

  Said but unsaid. That is the language of Alzheimer’s.

  ‘Carol increasingly lives in the present moment,’ Stuart continued. ‘I myself now live in the present moment. Because living in the moment is the best strategy for a carer. If you keep worrying about tomorrow, you’ll wear yourself out.’

  Since I’d last spoken to the couple, they’d kept up the fight–attending conferences and staying involved with the London research team (who they now call ‘family’)–adamantly refusing, as Stuart maintains, to ‘go gently into that good night’. As Stuart still works as a university chaplain, he’s ensured that somebody now goes to the house every day to check on Carol and her ninety-year-old mother, Joyce. He was telling me about how much more protective he is over Carol, how increasingly aware he is of the limited time she has left, how his life is now about ‘squeezing every last drop of her’ that he can.

  The trial Carol’s participating in is a form of immunotherapy, similar to the antibody drugs discussed in chapter six. It might not work. At her stage, it’s unlikely to. And she may only be getting a placebo (for the sake of scientific certitude, that information is also hidden from the scientists themselves). But the results no longer matter to the Jennings. ‘We’re not doing this for ourselves any more,’ said Stuart. ‘When she was diagnosed, Carol gave me very specific instructions. She’d said, “I want to be involved in research for as long as I possibly can.” So now, our struggle is the struggle to take the illness down with us.’

  We left the restaurant and walked through the park. Carol was scheduled for another brain scan and I agreed to accompany them as far as the hospital. The day was warm and clear. Elderly men and women reclined on wooden benches while young couples picnicked on the grass. There was a subtle confidence in Carol’s stride. Head raised, hands clasped behind her back, she was moving into the final stages with unusual calm. Perhaps the treatment was doing something, I mused. Then she looked at me and released a wide smile.

  Perhaps indeed.

  On a summer day in 2016, sitting alone in his house, Arnold Levi was stirred by the sound of Danie and me, once more waiting patiently at his doorstep. My meeting with Arnold was not to witness his decline–I already knew he wasn’t doing well–but to try to catch his final moments of memory and insight, his last tendrils of spirit and inner being.

  When I sat beside him and asked how he’d been, he returned a glassy, empty stare. He’d been busy at the film studio, he told me plainly. They needed help with a new production and he was the first person they called. Danie looked at me and gently shook his head. Arnold’s mind was now reliving his years as a young man, creating its own reality from residual memories, selecting and magnifying that which brought him the most peace in his life. He looked unnaturally formal, almost paralysed in a state of suspended animation, like a living statue.

  While Danie began his usual routine of opening Arnold’s mail, I accompanied Arnold to the kitchen to help him make a cup of tea. He watched with a calm, blank look as I reached for a cup and teaspoon. ‘Yes… yes…’ he quietly assured me, ‘that’s what we need… isn’t it?’

  ‘It says here the doctors want to see you again,’ Danie told Arnold as we walked back to the living room.

  ‘Oh,’ Arnold responded. ‘I wonder what they want to see me about…’

  ‘I know you’ve been taking your medication.’

  ‘Have I? Thank goodness you told me… I wouldn’t know what I was supposed to be doing… You know, I haven’t seen you in a long time.’

  Danie looked at him. ‘I saw you two days ago, Arnold.’

  ‘Oh… well, did I… did I know it?’

  I sensed fear in Arnold as he said this. He had the look of a man embroiled in a hopeless inner struggle, his brain searching for connections that no longer existed.

  ‘But why would I have forgotten that?’ he implored. ‘Is there any idea about that?’

  Danie interjected, ‘Why don’t you show
Joseph your photo albums? I’m sure he’d love to see them.’ On this bright note, arm-in-arm, Arnold and I headed up to the attic.

  ‘You can put your tea down on that desk,’ Arnold instructed, before planting himself on a chair in the corner beneath a small window that blanketed the floor in light. I pulled a large, leather-bound volume off a nearby shelf. The spine crackled as I opened it on Arnold’s lap, and he bristled at the sight. The first few pages held pictures of two children clasped in a pretty brunette’s arms. ‘That’s me and my mother and sister,’ he whispered with mild confidence. I turned the page to see photographs of a thirty-something, tanned, handsome Arnold in shorts on the beach. He was standing next to Danie’s parents–Danie himself, a small boy, nestled among them, grinning at the camera. Hoping to spark a flash of memory, I asked Arnold if he could name the people in the picture. He stared at them for a few seconds and then turned to me. ‘I can’t give you an answer to this…’ Then he looked over my shoulder. ‘Who’s left that tea there?’

  It was like watching someone endlessly fall back through time.

  My father had attempted this routine with Abbas. In what would become his final trip to visit his ailing father in Iran, he took several old photographs with him–memories of his childhood that he’d kept over the years. As with Arnold, they didn’t appear to trigger any signs of reminiscence in Abbas. And yet, I cannot think about that without feeling that we are missing something significant in our apprehension of memory. From one angle, my father’s photographs can be seen as mere snapshots of time–moments and experiences–to show Abbas that his past was real, that his life had meaning. From another, they are each an abstraction of the thoughts and feelings that must have occurred in Abbas when he experienced such moments, each a portrait that once hung proudly in the gallery of his mind, each something no amount of brain imaging or cell culturing or gene sequencing will ever recapitulate. When I contemplate my father’s act, and every other person no doubt doing the same, I see an attempt to tap into some distant, transient but surviving connection. It is not a futile endeavour. We do it because we know, deep down, a connection is still there.