In Pursuit of Memory

by Joseph Jebelli

  As Maria spoke, Alejandra appeared in the doorway and slowly walked in to sit opposite me. She’d been outside talking to Madrigal, who later told me that Alejandra had recently become volatile, even aggressive. A few days earlier, she’d tried to strangle her mother, and so it was important to assess her mood before introducing me. Not that Alejandra looked particularly dangerous. Baby-faced and doe-eyed, she looked at me with curiosity rather than suspicion.

  ‘I try my best here,’ she said to me in a stifled whisper, before asking, ‘Why is this happening inside my brain? The doctor says it’s because I’m changing… Yesterday I was thinking some things, and then suddenly, everything blanked… Is this correct? Is this normal?’ I assured her that scientists were doing everything they could. She returned a look I could not quite decipher: a frozen stare suggesting neither apprehension nor confusion. Gabriel repeated what I had said using different words, but it was as if he too needed a translator to bridge the divide. Although her memory was failing, language was clearly Alejandra’s most pressing concern.

  After a long silence she said, ‘Okay… I’m so sorry. The words are about to come… but they do not come… it’s like I have a gum, and the words get stuck to it… I want to speak well again… I want my words to get out like vomit; vomiting is easy, but the words are not.’ Then she looked directly at me. ‘I think about myself as a baby, like a baby trying to learn again. That’s how I feel.’

  E280A, the Paisa mutation, is thought to have entered Colombia through Spanish immigration; thirteen of the twenty-five families can be traced back to a Spanish conquistador in the seventeenth century.2 The mutation carriers are unique for a number of reasons. Some patients experience epilepsy, as well as a movement disorder called cerebral ataxia. They have an especially hard time remembering faces. And they become filled with what are known as ‘cotton wool’ plaques–large, ball-like structures that completely dislodge neighbouring brain regions. Moreover, imaging of their brains reveals an eye-catching hyperactivation of the hippocampus, visible years before memories fade, as if the hippocampus knows what’s coming and kicks into overdrive to protect itself, although if and how Paisa mutation-carriers perceive this is unknown. Education doesn’t appear to delay the symptoms; it merely leads to an earlier diagnosis. And they decline rapidly, often dying within four years instead of the average eight to ten.

  Carlos was only fifty when he died. In the months preceding his death he was mostly bedbound but could sometimes be found sitting in a corner, chewing raw sugar cane. When I asked Madrigal if these families were getting any extra help from the government, she laughed.

  ‘No,’ she said. ‘Welcome to Latin America.’

  ‘Look at this.’ Lopera spun in his chair and turned the computer screen towards me. ‘We’ve found that Paisa mutation-carriers show brain changes and signs of the Alzheimer’s in their blood as young as nine years old. As children.’ He spoke in a slow, lilting Spanish accent, and exuded a warm-heartedness I’ve come to expect from Colombians. (When I’d contacted him for the interview, he sent me a week-long agenda of patient visits and lab tours.) There was something intimate about the way he spoke of the Colombian families, too. Maybe it was his youth spent in similar circumstances: the son of a farmer and one of sixteen siblings facing stark poverty and an uncertain future. ‘With this kind of population,’ he continued, ‘we can study the natural evolution of the disease before the brain is completely destroyed.’

  Lopera now finds himself in a unique position. For the purpose of testing new drugs, the Colombian cohort has become the envy of scientists around the world. Nowhere else are so many people, all densely packed within the same locale, unambiguously bound for Alzheimer’s. It was more than a natural laboratory; it was a natural manufacturing complex. Among the first to recognise this were the California-based biotech firm Genentech and the Banner Alzheimer’s Institute in Arizona. In 2013 they began a five-year prevention study using a drug called Crenezumab–a new antibody designed to clear multiple forms of amyloid. If it works, the Colombians will be the first to receive it. ‘We’d be giving people at the highest imminent risk of Alzheimer’s access to treatment they wouldn’t otherwise have,’ Eric Reiman, executive director of the Banner Alzheimer’s Institute, told the New York Times.3

  Many participants are in their thirties, an age bracket Lopera considers viable for prevention trials. Like Henrik Zetterberg and now many others, he thinks that most clinical trials have been an exercise in shutting the stable door after the horse has bolted. ‘The biggest problem with Alzheimer’s research is that the pharmaceutical industry is primarily testing drugs in the clinical phase, when you don’t have much of a brain left. We need to work here’–he pointed to an image of a thirty-year-old brain that showed sparse deposits of amyloid–‘when the brain is more or less healthy.’

  Like many researchers, Lopera’s strategy is early detection using Henrik Zetterberg’s time-travelling biomarkers from chapter eight, followed by an intense regimen of amyloid therapy. The beauty of his trial is that a negative outcome would be almost as valuable as a positive one. This is because he knows, unequivocally, that if Crenezumab fails, it’s got something to do Crenezumab, not the trial candidates. Having so much wiggle room means he can also be more creative, and his next objective is to examine Paisa children, ranging from eight to sixteen years old, in order to build a timeline of Alzheimer’s unlike any other.

  When I left Lopera I made a note to touch base with him in a few years. The never-ending uncertainty of my quest often left me feeling as if I were chasing a shadow. But his is a quest with a concrete ending.

  The next day I left Medellín and made for the mountains. Winding up a steep and tortuous road–Gabriel driving while he and Madrigal talked Colombian politics–we were heading to Belmira, home to the first known Paisa-mutation family. This is dairy farming terrain, where cows and white Spanish bungalows dot the landscape and the sunlight, hitting the earth directly, makes the hills and everything around a brighter, almost luminescent green. We drove past motorcyclists hauling precarious loads and chivas (colourful buses without windows) ferrying people between towns. Wooden crosses and statues of the Virgin Mary were everywhere, and at 2,600 metres above sea level, a limitless vista of the city took shape below.

  Within two hours we had arrived in Belmira, a cluster of rough-hewn houses standing around a tall church, deep beneath the sharp, flora-laden slopes of the Andes. Walking through a small wooden gate, we were greeted by six dogs and eight cats and a short, bullnecked man pushing his way through them. Forty-seven-year-old Miguel Rodríguez lives here with his wife and two children. Home for the Rodríguez family is a wide, single-storey collection of rooms, each adorned with rosaries and Catholic memorabilia, separated by a large open courtyard. The garden was festooned with potted flowers, and strips of land where the family grow potatoes, corn, carrots and coriander.

  Miguel started developing severe symptoms three years ago. He and his twelve siblings are the offspring of Mr Rodríguez, Lopera’s first patient. So far, one sibling has died of the disease, and two others are currently sick. I shook Miguel’s hand and apologised, in Spanish, for my poor Spanish. He smiled broadly and released a mirthful laugh. His wife, Laura, then appeared and showed us into the sitting room. She had to guide Miguel to his chair; he moved with a shuffling gait and seemed quite unaware of his surroundings. Laura, now forty-five, was nineteen when she married Miguel. She said that he worked with livestock and never complained about his health. She first noticed the illness when he began talking to himself in the mirror and repeating himself in conversation. One day, she recalled, he had a cold and was wiping his nose, but the second he put the tissue in his pocket, he immediately brought it back out to use again; the cycle was so incessant she had to take it off him to prevent a nose rash.

  ‘When he wakes up in the morning, he forgets where the bathroom is,’ she said, while of the rest of the family huddled inside. Two of Miguel’s brothers were here, as wer
e his son, daughter and new daughter-in-law. He appeared vaguely aware that our conversation was about him, but Laura assured me this wasn’t a problem. Looking at me with a sort of quizzical affection, he suddenly pointed to a framed picture of Jesus Christ hanging on the wall.

  ‘He’s the boss.’

  ‘I know,’ I said, smiling.

  Laura continued. ‘He’s becoming a little aggressive.’

  ‘That’s a lie,’ Miguel instantly responded.

  ‘Sometimes I don’t understand what he’s saying—’

  ‘No, no, no,’ he proclaimed.

  ‘What do you like to do now?’ I asked, wanting to keep the mood light.

  ‘I work… I go to my job… That’s it,’ he replied, still smiling.

  Laura shook her head. ‘He stopped working five years ago. Now he just sits around and sleeps. He’s quite easy. Sometimes he gets lost.’

  ‘I cannot stand it,’ their daughter, Isabel, added. ‘My dad was really happy. He laughed with everyone. He loved playing football. But now he can’t do anything.’

  Miguel’s younger brother, Daniel, weighed in. ‘It’s cruel and sad, because there’s nothing for the family, and they’re the ones who suffer the most. He doesn’t know what’s happening to him. He’s become like a heavyweight child.’

  Two of Miguel’s sisters are participants in Lopera’s Crenuzumab trial. They’ve been on the drug for nine months. But the results are not due until 2020, and according to Lopera there’s been no discernible change to their symptoms. Eager for information, Daniel asked me plainly: based on all the research, what chances did I see for there being a cure in the near future?

  I took a moment to consider my answer. Then, head up, I explained how there was more cause for hope now than ever before. Because of families like his, I said, we’ve learned more in the last ten years than the past one hundred years. I told him how quickly discoveries are made now, and explained why the Colombian community may hold the key to finding the best possible drug. I also said that the next generation of drugs probably wouldn’t help his brother but might very well help his children. As for when, I gave him what I considered the most ambitious estimate without being unrealistic: ten years.

  He nodded slowly. ‘Thank you. Thank you for coming here. To be honest, I don’t have money to pay you. But before you leave, you must ride my horse.’

  In Colombian author Gabriel García Márquez’s multi-generational story of the Buendía family–One Hundred Years of Solitude, published in 1967–he describes the curse of Macondo, a fictional town whose inhabitants are beset by a loss of ‘the name and notion of things’. So striking is the condition’s likeness to Alzheimer’s, one can’t help but think the author spent time with the people of Belmira, Yarumal and Angostura, and that he possessed a considerable grasp of the disorder long before the rest of world ever did. Here’s just one passage:

  When his father told him about his alarm at having forgotten even the most impressive happenings of his childhood, Aureliano explained his method to him, and José Arcadio Buendía put it into practice all through the house and later on imposed it on the whole village. With an inked brush he marked everything with its name: table, chair, clock, door, wall, bed, pan. He went to the corral and marked the animals and plants: cows, goat, pig, hen, cassava, caladium, banana. Little by little, studying the infinite possibilities of a loss of memory, he realized that the day might come when things would be recognized by their inscriptions but that no one would remember their use. Then he was more explicit. The sign that he hung on the neck of the cow was an exemplary proof of the way in which the inhabitants of Macondo were prepared to fight against loss of memory: This is the cow. She must be milked every morning so that she will produce milk, and the milk must be boiled in order to be mixed with coffee to make coffee and milk. Thus they went on living in a reality that was slipping away, momentarily captured by words, but which would escape irremediably when they forgot the values of the written letters.

  The inhabitants of Belmira I met were certainly prepared to fight against the loss of memory. And when I left Colombia, I understood something else. That a populace in Iceland, a farmer in India, and a family in Colombia have joined the fight was surely a sign of impending success. The world was closing ranks around Alzheimer’s. There was nowhere left for it to hide.

  22

  Alzheimer’s Legacy

  Nothing in life is to be feared, it is only to be understood. Now is the time to understand more, so that we may fear less.

  Marie Curie, attributed

  WE’VE BEEN MARRIED fifty-one years. We got married in 1947.’ The old man’s voice echoed from the speakers in the dimly lit studio. ‘The first symptoms were memory loss. She seemed to forget things…’ He looked down, confused. ‘Gradually things got worse and worse… I really reached the end of the road, with having to get up in the morning, bathe her, dress her, deciding what clothes she’s going to put on, and then of course there are the meals to get ready. But the unfortunate thing is…’ He paused, voice crumbling, before letting the grief sink in, ‘is her not being able to even talk to me… It’s worse than anything I’ve come across.’

  Professor Nick Fox stopped the video. ‘It’s a dreadful disease,’ he said solemnly, turning to his audience. It was 24 April 2016. I was standing among a crowd of 100 preternaturally quiet Londoners in the Science Museum, watching a clip of one of Fox’s patients. It was 8 p.m.; the museum was holding an evening called ‘Lost in Thought’, a rallying cry for anyone who still hasn’t got the memo. Now, on the screen behind Fox, enormous photographs of Alois Alzheimer and Auguste Deter stood like columns, their story enshrined in the monolith of neuroscience.

  Fox has been an integral character in my story. It was he, and his protégée Natalie Ryan, both stellar neurologists at London’s National Hospital for Neurology and Neurosurgery, who had put me in touch with some of the Alzheimer’s families in this book. In addition to seeing patients, Fox now spends considerable time raising public awareness. He recently gave a talk preceding the performance of Nicola Wilson’s play Plaques and Tangles–portraying the life of a family affected by early-onset dementia–and had, in the past year, released simple online courses that the public could access to learn more about the condition.

  ‘One in three people in this room will get Alzheimer’s,’ Fox continued. ‘One in two will look after someone with Alzheimer’s.’ He paused and turned again. ‘As a society we’re sleepwalking into this.’

  And so it’s time to wake up. We can start by reassessing our priorities. Even though the disease is now heavily ingrained in the public’s collective consciousness, Alzheimer’s is still woefully underfunded. In the UK alone, the total cost of Alzheimer’s is £23 billion a year–more than cancer, heart disease and stroke combined–yet, incredibly, a mere 0.2 per cent of that is actually spent on research. John Trojanowski, a researcher at the University of Pennsylvania, has pointed out that the US spends more money on popcorn, Viagra and anti-ageing creams than Alzheimer’s research. This is astounding considering that an additional 7.7 million cases (that we know of) are reported every year. It seems a more horrifying kind of forgetting is taking place in our world. We are forgetting them.

  If things continue this way, epidemiologists estimate that the total number of Alzheimer’s cases will double every twenty years, making dementia the next global pandemic. In that event, the current 46 million patients would represent no more than the tip of a vast, society-crippling iceberg.

  So after a century of Alzheimer’s research, a journey that’s spanned the globe and brought with it a kaleidoscope of blind alleys, high hopes and stark tragedy, the final question is one that’s been with us from the very beginning. What is the future for this ‘peculiar’ disease?

  The answer might strike you as somewhat passive, but the hope, for the time being, is to reach where we currently are with diabetes. Diabetes was often a death sentence a century ago, but the advent of molecular biology, and subsequ
ent creation of synthetic human insulin from genetically engineered bacteria, has effectively reduced it to a phantom of its former self. Given how late in life Alzheimer’s usually strikes, its own phantom needn’t be a phantom for very long. Consider this: if Alzheimer’s could be delayed by only one year, there would be 9 million fewer people with the disease by 2050.1 A five-year delay, some scientists predict, would effectively halve the globe’s 46 million sufferers, saving healthcare services approximately $600 billion a year.2

  So what would this treatment look like? Based on everything we’ve seen in this book, in the future doctors may not need to administer extensive memory tests or rigorous brain imaging. A drop of blood or a strand of hair might foretell when our minds are set to unravel, and a doctor, with a host of genetically tailored pills to choose from, might know precisely which one to give to ensure lifelong brain health. No longer would we be at the mercy of what is written in our DNA, nor feel compelled to live a spartan existence. We would then be facing some new challenge, safe in the knowledge that memory is untouchable.

  In the meantime, here is what we know. We know Alzheimer’s is by and large an age-related disorder, but that ageing, in and of itself, is not the root cause. Alzheimer’s is, rather, the product of processes common in normal ageing. We know that plaques and tangles, for instance, are found in elderly people without causing disease; it’s only when they reach a certain threshold that they trigger full-blown dementia. We know that both are necessary–although perhaps not sufficient–to kill neurons, and we know that plaques appear before tangles and are therefore the most attractive target for drug developers.