A peculiar disease
In Pursuit of Memory is my attempt to understand what happened to my grandfather, and what is now happening to the 47 million people worldwide living with Alzheimer’s disease. The inspiration for the book was a collection of powerful memories and intuitions from my childhood: the memory of my grandfather staring with bewilderment at a family he no longer recognised, the memory of my father staring back with hopelessness engraved in his eyes, and the inescapable feeling that his symptoms weren’t just the hallmarks of old age.
From these foundations I tried to piece together the human story of this disease along with the scientific one – and explore the past, present and future of Alzheimer’s. In writing the book, and in researching the brain in the laboratory for more than a decade, I’ve interviewed many patients and patient relatives, each tirelessly edging scientists closer to a cure. As terrifying as the disease is, these brave souls know that for Alzheimer’s to be defeated we need only stand with those prepared to fight it.
What follows is an extract from this fight, and what turned out to become a global journey into the heart of Alzheimer’s – a biography of a disease borne of a devotion both to neuroscience and the memory of my grandfather.
Science is public, not private, knowledge.
Robert King Merton, Science, Technology and Society in Seventeenth-Century England, 1988
When I was twelve years old, my grandfather began to act strangely. I had known Abbas Jebelli as a self-effacing man, whose strong sense of family frequently carried him from volatile Iran to our quiet street in Bristol, England. He used to arrive with suitcases filled with pistachio nuts and Persian sweets, smiling until the corners of his eyes wrinkled as he handed us our gifts.
It started with inexplicable walks. When he was visiting, he’d leave the dinner table and then we would find him, half an hour later, aimlessly wandering the neighbourhood. ‘Please stop doing that,’ my father would say. ‘Bebakhshid,’ (‘forgive me’) was all Abbas ever replied in his native Farsi. His bright smiles were gradually replaced by a fearful, withdrawn expression, as if he’d lost something irreplaceable. Before long, he didn’t recognise his own family.
Something indefinably peculiar had happened to him.
As far as I knew, though, Abbas was just getting old. For decades, human lifespan had been rising. In the 1940s you’d be lucky to make it to age fifty, my father had explained, but we’re now living in the 1990s and Granddad was a leathery seventy-four-year-old whose mind, like his sight and nearly everything else, was slowly wearing out.
But that explanation never felt right. My young mind had no notion yet of the endless intricacies of the human brain, of the 100 billion cells that knit fragments of the past together into a ghostly tapestry that we call memory. Perhaps it was the sheer indiscriminateness of this bizarre affliction.Why, if this was ‘normal’, was my grandmother not going through the same thing? Why was the Queen still able to make such eloquent speeches on television when Abbas couldn’t even draw a clock face? Why, for that matter, wasn’t everyone who reached old age experiencing this?
Seventeen years later, I am standing in a small, dimly lit room in the Institute of Neurology at University College London. Glass beakers, pipettes, shelves filled with chemicals and reagents, and a large grey centrifuge surround me.The air is filled with the stinging scent of ethanol, and there’s a quiet hum as curtains of sterile air separate me from the nearby workstations. I stare into a small light microscope, focusing the image until the contours of numerous circular entities come into view. These are brain cells, taken from a rat, which I’m hoping will make some sense of what happened to my grandfather and millions of others just like him – all stricken by one of the most terrifying illnesses of modern times: Alzheimer’s disease.
The cells I’m looking at were already sick when I plated them two weeks ago; they’ve come from animals engineered to have the disease inscribed in their DNA. As expected, the now infamous plaques – dark patches that appear in the brains of Alzheimer’s patients, proposed to be the disease’s root cause twenty-five years ago – have started to form between them. But hidden among this neurological nightmare are the brain’s immune cells, microglia. And if the immune stimulant I’ve given them works, they could unleash a potent chemical attack on the plaques, physically engulfing and degrading them in a cellular defence mechanism called phagocytosis. Whether they will, though, still remains a question.
This theory is one of many that scientists are now testing, for Alzheimer’s is already a disease of global significance. It affects 47 million people worldwide and more than 800,000 in the UK alone. As the world’s population ages, Alzheimer’s is expected to affect 135 million people by 2050, overtaking cancer to become the second leading cause of death after heart disease. We’ve now reached a point at which almost everyone knows someone – whether a family member or a friend – who has been affected.
In recent years, cases from the echelons of high society have reached our ears as well. Rita Hayworth, Peter Falk, Charlton Heston, Rosa Parks, Margaret Thatcher – all eventually developed Alzheimer’s. When President Ronald Reagan was diagnosed, in November 1995, he published a handwritten letter to the American public: ‘At the moment I feel just fine. I intend to live the remainder of the years God gives me on this earth doing the things I have always done . . . Unfortunately, as Alzheimer’s disease progresses, the family often bears a heavy burden. I only wish there was some way I could spare Nancy from this painful experience.’
As anyone who has known a patient understands, Alzheimer’s is a merciless disease. It strips the mind of decades of stored memories that have been sculpted and embedded deep within our brains. Slowly and steadily, it erodes an individual’s autobiography, the very narrative that defines who we are. In his book The Emperor of All Maladies, Siddhartha Mukherjee describes cancer as ‘a distorted version of our normal selves’, ‘an individual – an enigmatic, if somewhat deranged, image in a mirror’. Perhaps, using this analogy, Alzheimer’s is the absence of a reflection altogether – a shadowy abyss that disengages a person from the world.
When I set out to study Alzheimer’s, it was for personal reasons. I never expected to cure the malady myself, but I did want to understand what happened to my grandfather after having to watch his memory disappear in this way. I learned quickly that the science behind the disease is still shrouded in mystery. Professor Alois Alzheimer, the eponymous German psychiatrist who first described it in 1906, called it ‘a peculiar disease’. He was referring mainly to its underlying pathology. Through the microscope Alzheimer had observed numerous plaques and tangles of an unknown substance.
But he didn’t know whether they were the disease’s root cause or just an after-effect. This question has remained unanswered, and we still know very little about what causes brain cell death on such a massive scale.
Here is what we do know. A person with Alzheimer’s is not ‘just getting old’. Their brain is under attack. A host of killer proteins has been unleashed – insidious black stains known as plaques and tangles. After gestating in the brain for years, perhaps decades, they will spread and hollow it out. In the hippocampus, a brain region crucial for memory, the plaques start by destroying the brain’s ability to create new memories by disrupting the electrical signals between neurons. As they grow in number, the plaques eventually trigger the rise of tangles – deformed proteins that completely unravel the neurons’ internal transport mechanism. The ensuing neurotoxic storm then causes the brain’s immune system to activate. But the damage is irreparable, and even our brain’s best efforts to remedy the affliction are insufficient. One by one, like a chain of dominoes, neurons continue to fall. In only a few years after symptom onset, neurons in the frontal lobe and cerebral cortex will start to perish, disrupting mood, spatial awareness, face-recognition and long-term memory. Six to eight years is usually how long it takes. The result is a brain the weight of an orange, having shrunk at three times the rate of normal ageing.
But there is hope. Today, advances in genetics and cell biology are changing the conceptual landscape of Alzheimer’s disease. Research has become highly collaborative: last year, for instance, more than 200 researchers from across Europe and the US worked together on a genetic study using 70,000 patients. The effort uncovered eleven new genes linked to Alzheimer’s disease, and armies of scientists continue to mobilise around the world in a concerted effort to unmask and disarm it. This book is, in part, a look at the fascinating and utterly important work they are doing. But this wasn’t enough for me. As time went on – as I moved through the ranks of postgraduate training, earning a doctorate in neuroscience and then becoming a postdoctorate researcher conducting independent research on neurodegeneration and mentoring my own students – I became convinced that studying Alzheimer’s would require something more than what I could discover in the laboratory. A paradox of biological research is that its practitioners invariably succumb to a strange form of tunnel vision: the more we delve into a problem, the more sheltered we are from its wider reach. I wanted to meet other people like my grandfather and his family, dealing with Alzheimer’s here and now, to tell the human story of this disease along with the scientific one.
Because more than anything, Alzheimer’s is a disease that affects families. Its symptoms engulf those around it, causing emotional turmoil for family members who can do nothing but watch while their loved ones – hearts still pumping, breath still flowing, eyes still open – slowly slip away for ever. I wondered how others were coping with this. Did their stories bear any resemblance to what my own family went through? To find answers I reached out to patients and families affected by the illness, including people with early-onset Alzheimer’s who, after inheriting it from their parents, have had to make unimaginable decisions and sacrifices throughout their lives.
One of the first patients I met was eighty-four-year-old Arnold Levi. Arnold represents a typical case of Alzheimer’s, and I listened as he and his carer, Danie, described the frighteningly tangible implications of this attack on Arnold’s brain. It happened slowly at first. He’d forget the same kind of things many elderly people do: names, dates, paying the bills, stocking the fridge. Small things. Ordinary things. No one thought much of it, least of all Arnold. But over the course of a few years people did start to think about it. His friends noticed an intense and unshakable decline in his behaviour. He needed help getting dressed. He left taps running, the burner on the stove on, the front door unlocked. And of course, he wasn’t trusted to drive any more.
And this was just the start. Over the next few years Arnold will become increasingly confused and agitated. His soaring level of forgetfulness and plummeting cognitive faculties will deeply frustrate him. Familiar people will seem like complete strangers. He may even frantically push them out the house, petrified by the ‘intruder’. Eventually, Arnold will no longer be able to speak, eat, drink or swallow. The most a loved one can hope for from the bedbound sufferer is the slightest quiver of comprehension from a tender touch or a cherished voice. Utterly robbed of his final years of life, Arnold will likely die of malnutrition or pneumonia, his mind now powerless to uphold the most primal rules of survival.
This is the horrifying reality of Alzheimer’s. Scientists talk about Alzheimer’s like detectives solving a crime – evidence versus speculation, deduction versus assumption, truth versus deception. We gather every clue we can before the brain cells we are studying vanish into thin air. At scientific meetings we ask questions about caveats and statistical significance. But Alzheimer’s isn’t like this for families. For us, it’s something terrifying and abstract: an invisible thief, a long goodbye we now know is not just old age, but of which many people know little else. Meeting these families, I realised that they wanted answers from me as badly as I did from them.
One thing was clear: if they were going to enlighten me, I’d make sure I returned the favour. Intensely, I started reading everything I could about the disease. My desk filled with stacks of research articles and academic papers. My inbox flooded with emails about the news and contents of the most august scientific journals. I contacted all my scientific colleagues to learn how the field was changing, and to keep pace with the lightning speed of research. I travelled across the globe, visiting different laboratories, interviewing scientists, and talking to patients and their families. I’ve had memory testing myself. I put all my powers of critical thinking from ten years of scientific training to the test. I was, in short, obsessed.
This is a book about the past, present and future of Alzheimer’s. I started my investigation from the very beginning, from the first recorded case more than 100 years ago, right up to the cutting- edge research being done today. It is a story as good as any detective novel. It took me to nineteenth-century Germany and post-war England; to the jungles of Papua New Guinea and the technological proving grounds of Japan; to America, India, China, Iceland, Sweden and Colombia; and to the cloud-capped spires of the most elite academic institutions. Its heroes are expert scientists from around the world – many of whom I have had the privilege of working with – and the incredibly brave patients and families who have changed the way scientists think about Alzheimer’s, unveiling a pandemic that took us centuries to track down, and, above all, reminding everyone never to take memory – our most prized possession, the faculty Jane Austen called ‘more wonderful’ than the rest – for granted.
Abbas didn’t live long with his illness. In Iran, like a candle burning itself out, his mind faded and vanished within seven years. It had reached an unknown destination, a place every patient I spoke to was heading and somewhere one in three people born in 2015 is bound for as well. I think about that nearly every day. It’s what has driven me forward.
Photo by Hajra Siraj.
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