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In Pursuit of Memory
The Fight Against Alzheimer's
Read by Thomas Judd
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Alzheimer’s is the great global epidemic of our time, affecting millions worldwide — there are more than 5 million people diagnosed in the US alone. And as our population ages, scientists are working against the clock to find a cure.
Neuroscientist Joseph Jebelli is among them. His beloved grandfather had Alzheimer’s and now he’s written the book he needed then — a very human history of this frightening disease. But In Pursuit of Memory is also a thrilling scientific detective story that takes you behind the headlines. Jebelli’s quest takes us from nineteenth-century Germany and post-war England, to the jungles of Papua New Guinea and the technological proving grounds of Japan; through America, India, China, Iceland, Sweden, and Colombia. Its heroes are scientists from around the world — many of whom he’s worked with — and the brave patients and families who have changed the way that researchers think about the disease.
This compelling insider’s account shows vividly why Jebelli feels so hopeful about a cure, but also why our best defense in the meantime is to understand the disease. In Pursuit of Memory is a clever, moving, eye-opening guide to the threat one in three of us faces now.
Preface: ‘A Peculiar Disease’
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 His bright smiles were gradually replaced by a fearful, withdrawn expression, as if he’d lost something irreplaceable.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 85 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.1 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.2 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.’3
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’.4 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.5 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.6 I think about that nearly every day. It’s what has driven me forward.
THE STORIES IN this book are real stories. Some patients have already received public attention for their illness and so were happy for me to use their real names. However, for reasons of anonymity, and because Alzheimer’s disease remains stigmatised in some parts of the world, other patients requested privacy. In these instances I have changed their names and identifying details. I ask the reader to respect their right to confidentiality.
The Psychiatrist with a Microscope
Idle old man,
That still would manage those authorities
That he hath given away!–Now, by my life,
Old fools are babes again…
William Shakespeare, King Lear
WHEN HE FINISHED his talk, Alois turned to the audience. There were nearly 100 guests in attendance, which usually assured a lively discussion. Alois–frank and commanding with a stout face, coiffed moustache, piercing gaze and immense stature–waited confidently. But no one spoke. Had they not understood him? Sensing an uncomfortable silence, the chairman intervened: ‘So there, respected colleague Alzheimer, I thank you for your remarks, clearly there is no desire for discussion.’
It was 3 November 1906. Dr Alois Alzheimer, a psychiatrist in Munich, was at the South-West German Psychiatrists’ meeting in Tübingen to describe a fifty-six-year-old woman with a peculiar and unexplained mental disorder. Her name was Auguste Deter.
Auguste had been brought to Alzheimer four years earlier by her husband Karl, a railroad worker who had spent the last eight months watching his wife’s behaviour deteriorate. The couple had been married for twenty-eight years, had one daughter, and were living a normal, healthy and happy life together.
But things changed when Auguste became inexplicably paranoid about the relationship between Karl and their female neighbour. More disturbing still was Auguste’s severe decline in memory. She was the epitome of a good German housewife, and so it struck Karl as highly unusual when she started neglecting her housework and making mistakes in the kitchen. Over the next few months Auguste wandered aimlessly round their apartment, hiding family possessions and speaking ominously of death. Her delusions resulted in panic when she started to believe that a carriage driver was trying to break into the apartment.
Karl was bewildered. At the time illnesses like this were extremely uncommon in someone of Auguste’s age, and overall rare in the population because living much beyond your sixties in 1901 was a rarity in itself. At a loss, Karl took his wife to one of the most highly regarded psychiatric clinics in the world: the Asylum for the Insane and Epileptic in Frankfurt, which had a nickname indicative of the attitudes towards mental illness at the time: ‘The Castle of the Insane’.
Auguste’s illness is the first reported case of what we now know as Alzheimer’s disease, the most common cause of dementia. Dementia is an umbrella term encompassing a constellation of brain disorders–such as vascular dementia, Lewy body dementia and fronto-temporal dementia–all of which involve a gradual loss in several aspects of cognition including memory, language, attention, orientation and problem solving. It often manifests as personality changes, depression, paranoia, agitation, delusions and even hallucinations.
The sheer breadth of faculties under assault fosters much confusion when faced with an Alzheimer’s victim. This was certainly true when it came to my grandfather. His four children, including my father, never truly accepted his diagnosis. They maintained that Abbas could be a curmudgeonly and somewhat eccentric character. They only recognised the term Alzheimer’s as something abstract–a hazy miscellany of a crumbling mind. Our family certainly had little concept of a cause of dementia, let alone the existence of dementia subtypes. We know now that to say someone has dementia is like saying they have cancer without identifying which type of cancer. And so, just as melanoma is a type of cancer, Alzheimer’s is a type of dementia.
We now know that Alzheimer’s is distinguished from other dementias by its unique effect on parts of the brain that control thought and memory, as well as its characteristic pattern of structural and chemical changes that can be seen with brain imaging and post-mortem examinations–appearing as catastrophic nerve cell death, and plaques and tangles of toxic proteins scattered throughout the brain. Plaques, in pure biological terms, are sticky proteins that clump together in the spaces between nerve cells. Tangles are also clumps of sticky proteins, but they form inside nerve cells and are more threadlike in appearance. Both are thought to be a kind of molecular ‘garbage’ that distorts healthy brain function and ultimately leads to Alzheimer’s. In truth, however, we’re still not entirely sure what they are, why they form, or how they cause the disease. This urgently needs to change. According to the World Health Organization (WHO), Alzheimer’s is now estimated to account for 70 per cent of all cases of dementia.1
But it took a long time to get this far.
For centuries, mental illness was thought to be the work of spirits and gods. In the book of Deuteronomy, the ancient Hebrews interpreted disordered thoughts as a curse from God for all who disobey Him: ‘The Lord will strike you with madness and blindness and confusion of mind.’2 Dementia was so poorly understood it was regarded along similar lines: those who had it were mad or just foolish. It was a time when unfounded beliefs held sway, and people tried to treat such illnesses by ‘trepanation’, drilling holes into the skull to release evil spirits. Greek and Roman philosophers sought to bring about a change through observation and scientific rationalism.
One of the earliest accounts of what we could call dementia was by the sixth-century BC mathematician Pythagoras, who described it as an inevitable outcome of old age; a period, in his words, where ‘the scene of mortal existence closes, after a great length of life, to which, very fortunately, few of the human species survive. The system returns to the imbecility of the first epoch of infancy.’3 The word ‘imbecility’ came from the Latin imbecillus, meaning ‘weak-minded’. According to Pythagoras, human life followed the seasons–old age is winter, and so its changes, however severe or unpleasant, were natural. But others thought there was more to it.
Cicero, the Roman philosopher, was among the most vital advocates in this regard. He thought dementia affected ‘only those who are weak in spirit and will’.4 A misguided theory of course, but it was the first whisper of the notion that dementia is not an inevitable product of old age. He took things further by suggesting that exercise might even prevent such decline, which was highly progressive given what I discuss later in this book. Building on his work, the Greek physician Aelius Galenus, better known as Galen, continued to buck conventional wisdom by describing patients suffering from what he called morosis (mental slowness), elderly people whose ‘knowledge of letters and arts are totally obliterated. Indeed, they can’t even remember their own names.’5 Galen shattered the ancient, irrational views his predecessors had created, recasting dementia as a medical problem worthy of deeper investigation.
However, the period that followed was almost disastrous. The Middle Ages saw a return to supernatural explanations for disease–dementia was a test of faith, a devil to be exorcised, a ‘consequence of the original sin’,6 and many sufferers were branded as witches. Even so, Christian-Judaeo beliefs also inspired a great deal of humanitarian thinking in the more enlightened. Brain diseases were looked upon with compassion and the care of the mentally ill became a religious obligation. Rational therapies, such as diets, baths and herbal medicines, came into practice: salad greens, barley water and milk, for example, were encouraged to replace red meat and wine; others endorsed a blend of aloes, black hellebore and colocynth.7
When the Enlightenment began, a string of discoveries in physics, chemistry and medicine–by Isaac Newton, Joseph Priestley, John Dalton, Luigi Galvani, Alessandro Volta and Edward Jenner–pointed towards the possibility of physical explanations for mental phenomena. The French philosopher René Descartes thought that experiences make tiny pores in the brain like needles making a pattern of holes in a linen cloth.8 David Hartley, the eighteenth-century English physician, claimed that nerve vibrations create sensations and memory, and that violent vibrations are the cause of mental illness.9 These ideas were vague and incomplete, but they were free of mysticism and the supernatural.
A tipping point arrived when the French psychiatrist Philippe Pinel became the first to separate discrete types of mental disorders from the broad-brush label of insanity; it was not good enough, he said, to call these patients ‘mad’. At the Bicêtre Hospital in Paris, Pinel called for compassion and non-violence when caring for the mentally ill. He spent hours talking to his patients and insisted that they be unshackled from their iron chains. Driven to study mental illness after the suicide of a close friend, Pinel used the term ‘dementia’ (démence, ‘out of one’s mind’) in 1797, ushering in the modern age of psychiatry.10 In 1838 his most talented student, Jean-Étienne Esquirol, fiercely denounced any remaining stigma: ‘A demented man has lost the goods he used to enjoy; he is a wealthy person turned poor. An idiot, by contrast, has always been unfortunate and poor.’11
Twenty-six years later, on 14 June 1864, Alois Alzheimer was born.
Alzheimer grew up in the small Bavarian town of Marktbreit, a place of fairy-tale houses and cobblestone streets, Roman castles and Catholic jurisprudence. His father, Eduard Alzheimer, was a lawyer who had lost his first wife to puerperal fever. After a year of grieving Eduard married her sister, Theresia, and the couple had six children together. Alois was the eldest.
In 1883, aged nineteen, he was the first in his family to apply to medical school and obtained a place at the University of Berlin, where the world’s brightest medical minds were already making history. It had been there, in 1858, that the humble-looking polymath Rudolf Virchow made great leaps in our understanding of basic biology. Virchow argued that cells, the basic structural unit of all organisms, were the roots of all disease. ‘The body,’ he wrote, ‘is a cell state in which every cell is a citizen. Disease is merely the conflict of the citizens of the state brought about by the action of external forces.’12
After five years of study surrounded by these ideas, Dr Aloysius ‘Alois’ Alzheimer was licensed to practise medicine for the German Empire. His interest was in psychiatry, so he applied for an intern position at the Frankfurt Mental Asylum and was chosen for the job on the same day the application was received. When Alzheimer arrived at the asylum there was certainly no shortage of work to be done. The director, Emil Sioli, desperately needed help after the asylum’s sole medical assistant retired and the only relief doctor on duty had accepted a job offer elsewhere. The twenty-four-year-old Alzheimer was faced with 254 patients and one exhausted mentor.
Though magnificent from the outside, the inside of the asylum was anything but. Like most things German at the time, it aimed to set the standard for ingenuity and so imposed the modern ‘non-restraint’ principle of treating patients, designed by the English psychiatrist John Conolly for a more humane treatment of the mentally ill. Straitjackets were forbidden. But as Alzheimer found out, this approach was not without its downsides: non-restraint also meant no forced feeding, bathing or cleaning. And with so many patients and so few staff, conditions soon spiralled out of control. As Alzheimer mused:
Everywhere cursing, spitting patients sat around in the corners, repulsive in their manner, peculiar in their dress, and completely inaccessible to the doctor. The most unclean habits were quite common. Some patients appeared with pockets filled with all sorts of waste, others had masses of paper and writing materials hidden all over the place and in big packets under their arms. When one had to finally follow the rules of hygiene and do something to get rid of the filth, one could not proceed without resistance and loud cries.13
Alzheimer immediately began to make changes. He introduced long baths where particularly uncontrollable patients could wind down; large consultation rooms where the doctors could talk and develop a dialogue with the patients; and special rooms designated solely for the microscopic examination of brain tissue. In this setting Alzheimer dived head first into research. Inspired by his years at Berlin University, he spent hours at the microscope, analysing hundreds of patient samples. The hunt for the biological origin of brain disease had begun.
- "An elegant, thorough, compelling and touchingly personal biography of the disease."—Wall Street Journal
- "An overview of Alzheimer's that never once sacrifices the human story for the scientific one. . . . Sensitive, humanizing, and poetic...a masterful overview of the disease."—NPR
- "Jebelli's exploration of the vexed science of Alzheimer's is lucid and emotionally rich in its portrayal of those who investigate the illness and those who endure it."—Publishers Weekly (starred review)
- "An elegant and precise writer, Jebelli follows every lead for a cure with the panache of a detective novelist, giving readers much to hope for despite the devastation Alzheimer's has left in its wake. Based on his meticulous and wide-ranging research, he makes a convincing argument that Alzheimer's will be defeated in the decades to come. Jebelli analyzes every facet of Alzheimer's with personal empathy and scientific rigor, a combination that makes for enthralling reading."—Kirkus (starred review)
- "In Pursuit of Memory is a remarkable combination of fine writing, personal honesty, and deep scientific insight - about a devastating and baffling disease that is becoming all too common. Jebelli weighs up all the evidence and all the theories about Alzheimer's and even allows us a glimpse of optimism about a cure."—Matt Ridley
- "Joseph Jebelli's wonderfully clear, vividly readable and comprehensive survey of the search for a cure . . . The world is closing in on Alzheimer's. There is nowhere left for it to hide."—The Times
- "A moving, sober and forensic study of the past, present and future of Alzheimer's from the point of view of a neurologist who has lived with the disease, at home and in the lab, from a very young age. The story Jebelli tells illustrates the tantalizing mystery of Alzheimer's: it's both highly visible yet agonizingly elusive...a timely analysis [that] might give comfort."—Observer
- "An accessible, diligently researched and well-travelled overview of the disease that is more deadly than cancer. Jebelli poignantly weaves the current science with the tragic stories of affected families, not least his own."—Sunday Times
"The definitive portrait of Alzheimer's disease - an illness that is rapidly becoming the defining plague of the 21st century."
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- Oct 31, 2017
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